Dihydroquinazolinone compound or pharmacologically acceptable salt, and cell growth inhibitor

ABSTRACT

Provided is a cell proliferation inhibitor comprising a compound of the formula (1) or a pharmacologically acceptable salt thereof:wherein J1 and J2 each represent CH or N, with the proviso that J1 and J2 are not simultaneously CH; r represents 0 to 4; each R101 is the same or different when r is 2 or more, and R101 represents a C1-6 alkyl group optionally substituted with a halogen atom or the like; s represents 0 to 5; each R102 is the same or different when s is 2 or more, and R102 represents a halogen atom or the like; R103 represents a hydrogen atom, a C1-6 alkyl group, a C3-6 cycloalkyl group, or a C3-6 cycloalkyl C1-6 alkyl group; and R101 and R103 are optionally linked together to form a five- to seven-membered ring hetero ring when R101 is present at the 8-position.

TECHNICAL FIELD

The present invention relates to a novel compound or a pharmacologicallyacceptable salt thereof and a cell proliferation inhibitor, specificallyto a novel dihydroquinazolinone-based compound which has tankyraseinhibitory activity and/or microtubule inhibitory activity, apharmacologically acceptable salt thereof, and a tankyrase inhibitor, amicrotubule inhibitor and a pharmaceutical composition comprising thedihydroquinazolinone-based compound or pharmacologically acceptable saltthereof.

BACKGROUND ART

Poly(ADP-ribosyl)ation is a biochemical reaction which is a chainaddition of ADP-ribose to glutamic acid or aspartic acid residues of aprotein, with nicotinamide adenine dinucleotide as a substrate. Aproduced poly(ADP-ribose) chain is composed of about 200 ADP-riboses atlongest. A poly(ADP-ribose) polymerase (PARP) family is known as anenzyme which catalyzes the poly(ADP-ribosyl)ation reaction.

Of the PARP family, PARP-5a and PARP-5b are called tankyrase-1 andtankyrase-2, respectively. Normally, in many cases, both enzymes aresimply called tankyrase collectively. The tankyrase is composed of anankyrin region which recognizes a protein which is to bepoly(ADP-ribosyl)ated; a sterile alpha motif (SAM) region which isinvolved in self-multimerization; and a PARP catalytic domain whichcontrols the poly(ADP-ribosyl)ation reaction.

The tankyrase binds to various proteins through the ankyrin region inthe molecule to poly(ADP-ribosyl)ates these proteins. Examples oftankyrase-bound proteins include TRF1, NuMA, Plk1, Miki, Axin, TNKS1BP1,IRAP, McI-1 and 3BP2. The tankyrase poly(ADP-ribosyl)ates these proteinsto regulate the physiological functions of the proteins. Hence,inhibition of tankyrase is considered to be effective for the control ofcell proliferation, cell differentiation, tissue formation and the likewhich are the physiological functions of the proteins.

Examples of known tankyrase inhibitory compounds having tankyraseinhibitory activity include the compound XAV939 described in Non PatentLiterature 1 (Huang SM. et al., Nature, Vol. 461, pp. 614-620, 2009),the compounds described in Patent Literature 1 (WO 2013/117288) andPatent Literature 2 (WO 2013/182580), NVP-TNKS656 described in NonPatent Literature 2 (Michael D. Shultz et al., Journal of MedicinalChemistry, 56, pp. 6495-6511, 2013), and G007-LK described in Non PatentLiterature 3 (Andrew Voronkov. et al., Journal of Medicinal Chemistry,56, pp. 3012-3023, 2013) and Patent Literature 3 (WO 2012/076898).

A microtubule is a protein forming a cytoskeleton, and is involved information of a spindle in the phase of cell division period, formationand maintenance of cellular morphology, arrangement of intracellularorganelles and transport of substances to the organs, axonal transportin nerve cells, and the like. The microtubule is composed of tubulindimers each composed of an α-subunit and a β-subunit. A process in whichthe dimers aggregate to form a microtubule is referred to aspolymerization, and a process in which a microtubule reverts to atubulin is referred to as depolymerization.

As microtubule inhibitors which inhibit microtubules, microtubuledepolymerization inhibitors for promoting the polymerization tostabilize and excessively form microtubules, and microtubulepolymerization inhibitors for inhibiting the polymerization are known,and these microtubule inhibitors each suppress cell proliferation bydisrupting the state of dynamic equilibrium of microtubulepolymerization to arrest the cell cycle in the M phase. As suchmicrotubule inhibitors, paclitaxel, vinblastine, vincristine, vindesine,vinorelbine, docetaxel, cabazitaxel, eribulin and the like are known.These microtubule inhibitors are commercially available as agents havingan antitumor effect on leukemia, malignant lymphoma and malignanttumors.

Such tankyrase inhibitors and microtubule inhibitors are considered tohave an effect against fibrosarcoma, ovary cancer, glioblastoma,pancreatic cancer, breast cancer, astrocytoma, lung cancer, gastriccancer, hepatocyte cancer, multiple myeloma, colorectal cancer, bladdercancer, leukemia, infections with a Herpes simplex virus, anEpstein-Barr virus and the like, fibroses such as pulmonary fibrosis,cherubism, multiple sclerosis, amyotrophic lateral sclerosis, skin andcartilage injuries, metabolic diseases and the like, and a suppressiveeffect on cancer metastasis. Development of a new pharmaceutical productfor preventing and/or treating the above-mentioned diseases is desired.

CITATION LIST Patent Literature

-   Patent Literature 1: WO 2013/117288-   Patent Literature 2: WO 2013/182580-   Patent Literature 3: WO 2012/076898

Non Patent Literature

-   Non Patent Literature 1: Huang SM. et al., Nature, Vol. 461, pp.    614-620, 2009-   Non Patent Literature 2: Michael D. Shultz et al., Journal of    Medicinal Chemistry, 56, pp. 6495-6511, 2013-   Non Patent Literature 3: Andrew Voronkov. et al., Journal of    Medicinal Chemistry, 56, pp. 3012-3023, 2013

SUMMARY OF INVENTION Technical Problem

The present invention has been made in view of the problems of theconventional techniques, and an object of the present invention is toprovide a novel compound which has excellent tankyrase inhibitoryactivity and/or microtubule inhibitory activity and which is useful fortreatment and/or prevention of, for example, proliferative diseases suchas cancer, and also useful for treatment of Herpes virus infection,multiple sclerosis, sugar metabolism disease, skin and cartilagedamages, pulmonary fibrosis and the like; a pharmacologically acceptablesalt thereof; and a cell proliferation inhibitor, a tankyrase inhibitor,a microtubule inhibitor and a pharmaceutical composition which haveexcellent tankyrase inhibitory activity and/or microtubule inhibitoryactivity. Another object of the present invention is to provide a methodfor producing the novel compound or a pharmacologically acceptable saltthereof, and an intermediate compound useful for the production thereof.

Solution to Problem

The present inventors have extensively conducted studies for solving theabove-described problems, and resultantly found that adihydroquinazolinone-based compound having a specific structure, and apharmacologically acceptable salt thereof have excellent tankyraseinhibitory activity and/or microtubule inhibitory activity. Accordingly,the present invention has been completed.

That is, the present invention includes the following.

A cell proliferation inhibitor, comprising a compound of the formula (1)or a pharmacologically acceptable salt thereof as an active ingredient:

wherein J¹ and J² each represent CH or N, with the proviso that J¹ andJ² are not simultaneously CH;

r represents 0 to 4;

each R¹⁰¹ is the same or different when r is 2 or more, and represents ahalogen atom, a C₁₋₆ alkyl group optionally substituted with a halogenatom, OR¹¹¹, or a group represented by the formula:—N(R^(112a))—R^(112b),

where R¹¹¹, R^(112a) and R^(112b) are each independently a hydrogen atomor a C₁₋₆ alkyl group;

s represents 0 to 5;

each R¹⁰² is the same or different when s is 2 or more, and represents ahalogen atom, a C₁₋₆ alkyl group, OR¹¹³, a group represented by theformula: —N(R^(114a))—R^(114b), a group represented by the formula:—NH—C(═O)—R¹¹⁵, a group represented by the formula: —C(═O)—R¹¹⁶, anoptionally substituted aryl group, an optionally substituted heteroarylgroup, a nitro group, or a cyano group,

where R¹¹³ is a hydrogen atom, an optionally substituted alkyl group, anoptionally substituted aryl group, an optionally substituted arylalkylgroup, or an optionally substituted heteroaryl group,

R^(114a) and R^(114b) are each independently a hydrogen atom or a C₁₋₆alkyl group,

R¹¹⁵ is an optionally substituted alkyl group, an optionally substitutedaryl group, an optionally substituted heteroaryl group, or a grouprepresented by the formula: —NH—R¹²¹,

R¹¹⁶ is an optionally substituted alkyl group, an optionally substitutedaryl group, an optionally substituted heteroaryl group, OR¹²², or agroup represented by the formula: —N(R^(123a))—R^(123b),

R¹²¹ is an optionally substituted alkyl group, an optionally substitutedaryl group, or an optionally substituted heteroaryl group,

R¹²² is a hydrogen atom, an optionally substituted alkyl group, anoptionally substituted aryl group, or an optionally substitutedheteroaryl group, and

R^(123a) and R^(123b) are each independently a hydrogen atom, anoptionally substituted alkyl group, an optionally substituted arylgroup, or an optionally substituted heteroaryl group, or R^(123a) andR^(123b) are linked together to form a cyclic amine;

R¹⁰³ represents a hydrogen atom, a C₁₋₆ alkyl group, a C₃₋₆ cycloalkylgroup, or a C₃₋₆ cycloalkyl C₁₋₆ alkyl group; and

R¹⁰¹ and R¹⁰³ are optionally linked together to form a five- toseven-membered ring hetero ring when R¹⁰¹ is present at the 8-position.

[2] The cell proliferation inhibitor according to [1], wherein in theformula (1), r is 0; or r is 1, R¹⁰¹ is present at the 7-position or the8-position and R¹⁰¹ represents a C₁₋₃ alkyl group optionally substitutedwith a halogen atom, or a hydroxy group; or r is 1, R¹⁰¹ is present atthe 8-position and R¹⁰¹ and R¹⁰³ are linked together to form a five- orsix-membered ring hetero ring.[3] The cell proliferation inhibitor according to [1] or [2], wherein inthe formula (1), R¹⁰³ represents a hydrogen atom, a C₁₋₃ alkyl group ora C₃₋₆ cycloalkyl C₁₋₃ alky group; or r is 1, R¹⁰¹ is present at the8-position and R¹⁰¹ and R¹⁰³ are linked together to form a five- orsix-membered ring hetero ring.[4] The cell proliferation inhibitor according to any one of [1] to [3],wherein in the formula (1), s is 0; or s is 1 and R¹⁰² represents ahalogen atom, OR¹¹³ in which R¹¹³ is an optionally substituted C₁₋₃alkyl group, or an optionally substituted aryl group.[5] The cell proliferation inhibitor according to any one of [1] to [4],wherein in the formula (1), J¹ and J² each represent N.[6] The cell proliferation inhibitor according to any one of [1] to [5],wherein the cell proliferation inhibitor is a tankyrase inhibitor.[7] The cell proliferation inhibitor according to any one of [1] to [6],wherein the cell proliferation inhibitor is a microtubule inhibitor.[8] The cell proliferation inhibitor according to any one of [1] to [7],wherein the cell proliferation inhibitor is a pharmaceuticalcomposition.[9] The cell proliferation inhibitor according to [8], wherein the cellproliferation inhibitor is a prophylactic and/or therapeutic agent forat least one selected from the group consisting of malignant tumor,Herpes simplex virus infection, Epstein-Barr virus infection, pulmonaryfibrosis, multiple sclerosis and amyotrophic lateral sclerosis.[10] A compound of the formula (1a) or a pharmacologically acceptablesalt thereof:

wherein J¹ and J² each represent CH or N, with the proviso that J¹ andJ² are not simultaneously CH;

r represents 0 to 4;

each R¹⁰¹ is the same or different when r is 2 or more, and represents ahalogen atom, a C₁₋₆ alkyl group optionally substituted with a halogenatom, OR¹¹¹, or a group represented by the formula:—N(R^(112a))—R^(112b),

where R¹¹¹, R^(112a) and R^(112b) are each independently a hydrogen atomor a C₁₋₆ alkyl group;

s represents 0 to 5;

each R¹⁰² is the same or different when s is 2 or more, and represents ahalogen atom, a C₁₋₆ alkyl group, OR¹¹³, a group represented by theformula: —N(R^(114a))—R^(114b), a group represented by the formula:—NH—C(═O)—R¹¹⁵, a group represented by the formula: —C(═O)—R¹¹⁶, anoptionally substituted aryl group, an optionally substituted heteroarylgroup, a nitro group, or a cyano group,

where R¹¹³ is a hydrogen atom, an optionally substituted alkyl group, anoptionally substituted aryl group, an optionally substituted arylalkylgroup, or an optionally substituted heteroaryl group,

R^(114a) and R^(114b) are each independently a hydrogen atom or a C₁₋₆alkyl group,

R¹¹⁵ is an optionally substituted alkyl group, an optionally substitutedaryl group, an optionally substituted heteroaryl group, or a grouprepresented by the formula: —NH—R¹²¹,

R¹¹⁶ is an optionally substituted alkyl group, an optionally substitutedaryl group, an optionally substituted heteroaryl group, OR¹²², or agroup represented by the formula: —N(R^(123a))—R^(123b),

R¹²¹ is an optionally substituted alkyl group, an optionally substitutedaryl group, or an optionally substituted heteroaryl group,

R¹²² is a hydrogen atom, an optionally substituted alkyl group, anoptionally substituted aryl group, or an optionally substitutedheteroaryl group, and

R^(123a) and R^(123b) are each independently a hydrogen atom, anoptionally substituted alkyl group, an optionally substituted arylgroup, or an optionally substituted heteroaryl group, or R^(123a) andR^(123b) are linked together to form a cyclic amine;

R¹⁰³ represents a hydrogen atom, a C₁₋₆ alkyl group, a C₃₋₆ cycloalkylgroup, or a C₃₋₆ cycloalkyl C₁₋₆ alkyl group; and

R¹⁰¹ and R¹⁰³ are optionally linked together to form a five- toseven-membered ring hetero ring when R¹⁰¹ is present at the 8-position,

with the exception of cases where J¹ represents CH, J² represents N, ris 0, R¹⁰³ is a hydrogen atom or a methyl group, R¹⁰² is present at thep-position, and R¹⁰² is a methoxy group.

[11] The compound according to [10] or a pharmacologically acceptablesalt thereof, wherein in the formula (1a), r is 0; or r is 1, R¹⁰¹ ispresent at the 7-position or the 8-position and R¹⁰¹ represents a C₁₋₃alkyl group optionally substituted with a halogen atom, or a hydroxygroup; or r is 1, R¹⁰¹ is present at the 8-position and R¹⁰¹ and R¹⁰³are linked together to form a five- or six-membered ring hetero ring.[12] The compound according to [10] or [11] or a pharmacologicallyacceptable salt thereof, wherein in the formula (1a), R¹⁰³ represents ahydrogen atom, a C₁₋₃ alkyl group or a C₃₋₆ cycloalkyl C₁₋₃ alky group;or r is 1, R¹⁰¹ is present at the 8-position and R¹⁰¹ and R¹⁰³ arelinked together to form a five- or six-membered ring hetero ring.[13] The compound according to any one of [10] to [12] or apharmacologically acceptable salt thereof, wherein in the formula (1a),s is 0; or s is 1 and R¹⁰² represents a halogen atom, OR¹¹³ in whichR¹¹³ is an optionally substituted C₁₋₃ alkyl group, or an optionallysubstituted aryl group.[14] A tankyrase inhibitor comprising the compound according to any oneof [10] to [13] or a pharmacologically acceptable salt thereof as anactive ingredient.[15] A microtubule inhibitor comprising the compound according to anyone of [10] to [13] or a pharmacologically acceptable salt thereof as anactive ingredient.[16] A pharmaceutical composition comprising the compound according toany one of [10] to [13] or a pharmacologically acceptable salt thereofas an active ingredient.[17] A prophylactic and/or therapeutic agent for a disease attributableto tankyrase and/or microtubules, comprising at least one compoundselected from the group consisting of a compound of the formula (1), acompound of the formula (1a) and a pharmacologically acceptable saltthereof as an active ingredient.[18] A method for inhibiting tankyrase, comprising administering to apatient at least one compound selected from the group consisting of acompound of the formula (1), a compound of the formula (1a) and apharmacologically acceptable salt thereof, or the cell proliferationinhibitor according to [1].[19] A method for inhibiting microtubules, comprising administering to apatient at least one compound selected from the group consisting of acompound of the formula (1), a compound of the formula (1a) and apharmacologically acceptable salt thereof, or the cell proliferationinhibitor according to [1].[20] A method for treating a disease attributable to tankyrase and/ormicrotubules, comprising administering to a patient at least onecompound selected from the group consisting of a compound of the formula(1), a compound of the formula (1a) and a pharmacologically acceptablesalt thereof, or the cell proliferation inhibitor according to [1].[21] A compound of the formula (1) or a pharmacologically acceptablesalt thereof, for use in inhibiting tankyrase and/or inhibitingmicrotubules.[22] A compound of the formula (1) or a pharmacologically acceptablesalt thereof, for use in treating a disease attributable to tankyraseand/or microtubules.

Advantageous Effects of Invention

According to the present invention, it is possible to provide a novelcompound which has excellent tankyrase inhibitory activity and/ormicrotubule inhibitory activity and which is effective against diseasesrelated to tankyrase and/or microtubules; a pharmacologically acceptablesalt thereof; and a cell proliferation inhibitor, a tankyrase inhibitor,a microtubule inhibitor and a pharmaceutical composition which haveexcellent tankyrase inhibitory activity and/or microtubule inhibitoryactivity. It is also possible to provide a method for producing thenovel compound or a pharmacologically acceptable salt thereof, and anintermediate compound useful for the production thereof.

Examples of the diseases related to tankyrase and/or microtubulesinclude, but are not limited to, various solid tumors and blood tumors,for example, malignant tumors such as fibrosarcoma, ovary cancer,glioblastoma, pancreatic cancer, breast cancer, astrocytoma, lungcancer, gastric cancer, liver cancer, colorectal cancer, bladder cancerand leukemia; infections such as Herpes simplex virus infection andEpstein-Barr virus infection; fibroses such as pulmonary fibrosis;neurodegenerative diseases such as multiple sclerosis and amyotrophiclateral sclerosis; and various types of inflammatory diseases such asskin and cartilage damages.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1A shows the results of conducting a microtubule polymerizationinhibition test of compounds prepared in Examples 65, 69 and 70(compound concentration: 3 μM).

FIG. 1B shows the results of conducting a microtubule polymerizationinhibition test of the compounds prepared in Examples 65, 69 and 70(compound concentration: 15 μM).

DESCRIPTION OF EMBODIMENTS

The present invention provides a cell proliferation inhibitor comprisinga compound of the formula (1) or a pharmacologically acceptable saltthereof as an active ingredient:

wherein J¹ and J¹ each represent CH or N, with the proviso that J¹ andJ² are not simultaneously CH;

r represents 0 to 4;

each R¹⁰¹ is the same or different when r is 2 or more, and represents ahalogen atom, a C₁₋₆ alkyl group optionally substituted with a halogenatom, OR¹¹¹, or a group represented by the formula:—N(R^(112a))—R^(112b),

where R¹¹¹, R^(111a) and R^(112b) are each independently a hydrogen atomor a C₁₋₆ alkyl group;

s represents 0 to 5;

each R¹⁰² is the same or different when s is 2 or more, and represents ahalogen atom, a C₁₋₆ alkyl group, OR¹¹³, a group represented by theformula: —N(R^(114a))—R^(114b), a group represented by the formula:—NH—C(═O)—R¹¹⁵, a group represented by the formula: —C(═O)—R¹¹⁶, anoptionally substituted aryl group, an optionally substituted heteroarylgroup, a nitro group, or a cyano group,

where R¹¹³ is a hydrogen atom, an optionally substituted alkyl group, anoptionally substituted aryl group, an optionally substituted arylalkylgroup, or an optionally substituted heteroaryl group,

R^(114a) and R^(114b) are each independently a hydrogen atom or a C₁₋₆alkyl group,

R¹¹⁵ is an optionally substituted alkyl group, an optionally substitutedaryl group, an optionally substituted heteroaryl group, or a grouprepresented by the formula: —NH—R¹²¹,

R¹¹⁶ is an optionally substituted alkyl group, an optionally substitutedaryl group, an optionally substituted heteroaryl group, OR¹²², or agroup represented by the formula: —N(R^(123a))—R^(123b),

R¹²¹ is an optionally substituted alkyl group, an optionally substitutedaryl group, or an optionally substituted heteroaryl group,

R¹²² is a hydrogen atom, an optionally substituted alkyl group, anoptionally substituted aryl group, or an optionally substitutedheteroaryl group, and

R^(123a) and R^(123b) are each independently a hydrogen atom, anoptionally substituted alkyl group, an optionally substituted arylgroup, or an optionally substituted heteroaryl group, or R^(123a) andR^(123b) are linked together to form a cyclic amine;

R¹⁰³ represents a hydrogen atom, a C₁₋₆ alkyl group, a C₃₋₆ cycloalkylgroup, or a C₃₋₆ cycloalkyl C₁₋₆ alkyl group; and

R¹⁰¹ and R¹⁰³ are optionally linked together to form a five- toseven-membered ring hetero ring when R¹⁰¹ is present at the 8-position.The present invention also provides a compound of the formula (1a) or apharmacologically acceptable salt thereof:

wherein J¹, J², r, R¹⁰¹, s, R¹⁰² and R¹⁰³ are each independently thesame as J¹, J², r, R¹⁰¹, s, R¹⁰² and R¹⁰³ in the formula (1),respectively, with the exception of cases where J¹ represents CH, J²represents N, r is 0, R¹⁰³ is a hydrogen atom or a methyl group, R¹⁰² ispresent at the p-position, and R¹⁰² is a methoxy group.

In the present invention, the “dihydroquinazolinone-based compound”refers to a compound in which a hydrogen atom or a substituent ispartially added at the 1-position and the 2-position of quinazolinone;or a salt thereof. In the present invention, unless otherwise specified,the number associated with “position” in the formulas (1) and (1a)indicates a position number at which R¹⁰¹ is substituted in thedihydroquinazolinone-based compound, and a position number ofquinazolinone is directly applied to the position number. Further, inthe present invention, unless otherwise specified, the alphabet (o, m orp) associated with “position” in the formulas (1) and (1a) indicates aposition number of a benzene substituent with which R¹⁰ is substituted.

In the formulas (1) and (1a), the “hydrogen atoms” include deuteriumatoms (D). In the formulas (1) and (1a), the “halogen atoms” includefluorine atoms, chlorine atoms, bromine atoms and iodine atoms.

In the formulas (1) and (1a), the “alkyl group” refers to a linear orbranched saturated hydrocarbon group having 1 to 8 carbon atoms.Examples of the linear or branched saturated hydrocarbon group generallyinclude, but are not particularly limited to, groups such as methyl,ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl,n-pentyl, isopentyl, neopentyl and n-hexyl groups. Of these, “C₁₋₆ alkylgroups” having 1 to 6 carbon atoms are preferable, and “C₁₋₃ alkylgroups” having 1 to 3 carbon atoms are more preferable, as the “alkylgroup” according to the present invention.

In the formulas (1) and (1a), the “aryl group” refers to a six-memberedring monocyclic aromatic hydrocarbon group consisting of only carbonatoms, or a fused-ring aromatic hydrocarbon group in which two or moresuch six-membered ring monocyclic aromatic hydrocarbon groups are fused.Examples of the aryl group generally include, but are not particularlylimited to, groups such as phenyl and naphthyl groups. Of these,monocyclic aromatic hydrocarbon groups (phenyl groups) are preferable asthe “aryl group” according to the present invention.

In the formulas (1) and (1a), the “heteroaryl group” refers to a groupderived from a five- or six-membered ring monocyclic aromaticheterocycle having 1 to 4 hetero atoms selected from the groupconsisting of a nitrogen atom, an oxygen atom and a sulfur atom; a groupderived from a fused-ring aromatic heterocycle in which a five- orsix-membered ring monocyclic aromatic heterocycle having 1 to 4 heteroatoms is fused with a six-membered ring monocyclic aromatic ringconsisting of only carbon atoms; or a group derived from a fused-ringaromatic heterocycle in which a five- or six-membered ring monocyclicaromatic heterocycle having 1 to 4 hetero atoms is fused with a five- orsix-membered ring monocyclic aromatic heterocycle having 1 to 4 heteroatoms. Examples of the heteroaryl group generally include, but are notparticularly limited to, groups such as pyrrolyl, pyrazolyl, furyl,thienyl, oxazolyl, imidazolyl, isoxazolyl, thiazolyl, isothiazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, tetrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl,pyridyl, pyridazinyl, pyrazyl, pyrimidyl, benzothienyl, benzofuryl,indolyl, isoindolyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl,benzoxazolyl, benzotriazolyl, quinolyl, isoquinolyl, quinoxalinyl,quinazolinyl, phthalazinyl, imidazo[5,1-b]thiazolyl and1H-pyrrolo[2,3-b]pyridinyl groups, each of which has a binding site atany possible position. Of these, quinolyl, isoquinolyl and1H-pyrrolo[2,3-b]pyridinyl, each of which has a binding site at anypossible position, are preferable as the “heteroaryl group” according tothe present invention.

In the general formulas (1) and (1a), the “cycloalkyl group” refers to asaturated hydrocarbon group (cyclic hydrocarbon group) having 3 to 8carbon atoms, and the cyclic hydrocarbon group may be a monocyclic ring,or may form a fused ring, a crosslinked ring or a spiro ring. Examplesof the cyclic saturated hydrocarbon group generally include, but are notparticularly limited to, groups such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[3.1.0]hexyl,bicyclo[3.2.0]heptyl, bicyclo[4.1.0]heptyl, bicyclo[4.2.0]octyl,bicyclo[3.3.0]octyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl,bicyclo[3.1.1]heptyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl,bicyclo[2.2.2]octyl, spiro[2.3]hexyl, spiro[2.4]heptyl, spiro[2.5]octyl,spiro[3.3]heptyl and spiro[3.4]octyl groups, each of which has a bindingsite at any possible position. Of these, monocyclic cycloalkyl groupsare preferable, “C₃₋₈ cycloalkyl groups” having 3 to 8 carbon atoms aremore preferable, and C₃₋₆ cycloalkyl groups” having 3 to 6 carbon atomsare still more preferable, as the “cycloalkyl group” according to thepresent invention.

In the formulas (1) and (1a), the “hetero ring” refers to an unsaturatedheterocycle other than an aromatic ring, which has 1 to 4 hetero atomsselected from the group consisting of a nitrogen atom, an oxygen atomand a sulfur atom, and the hetero ring is preferably five- toseven-membered ring ring, more preferably five- or six-membered ringring. The heterocycle may be a monocyclic ring, or may form acrosslinked ring or a spiro ring. Examples of the “five- toseven-membered ring heterocycle” include, but are not particularlylimited to, rings such as 2,3-dihydro-1H-pyrrole, 2,3-dihydrooxazole,2,3-dihydro-1H-imidazole, 1,2,3,4-tetrahydropyridine,2,3,4,5-tetrahydro-1H-azepine, 3,4-dihydro-2H-1,4-oxazine,1,2,3,4-tetrahydropyrazine, 3,4-dihydro-2H-1,4-thiazine and4,5,6,7-tetrahydro-1,4-oxazepine rings, each of which has a binding siteat any possible position. Of these, 2,3-dihydro-1H-pyrrole,1,2,3,4-tetrahydropyrazine and 3,4-dihydro-2H-1,4-oxazine, each of whichhas a binding site at any possible position, are preferable as the“five- to seven-membered ring hetero ring” according to the presentinvention.

In the present invention, the “heterocycloalkyl group” refers to athree- to seven-membered ring saturated heterocycle or unsaturatedheterocycle other than an aromatic ring, which has 1 to 4 hetero atomsselected from the group consisting of a nitrogen atom, an oxygen atomand a sulfur atom, and the heterocycle may be a monocyclic ring, or mayform a crosslinked ring or a spiro ring. Examples of theheterocycloalkyl group include, but are not particularly limited to,groups such as oxetanyl, tetrahydrofuryl, dihydrofuryl, dihydropyranyl,tetrahydropyranyl, 1,3-dioxanyl, 1,4-dioxanyl, aziridinyl, azetidinyl,pyrrolidinyl, piperidinyl, piperazinyl, 1,1-dioxide thiomorphorinyl,dioxopiperazinyl, diazepanyl, morphorinyl, 1,3-dioxolanyl,imidazolidinyl, imidazolinyl, pyrrolinyl, oxathiolanyl, dithiolanyl,1,3-dithianyl, 1,4-dithianyl, oxathianyl, thiomorphorinyl,3,6-diazabicylo[3.1.1]heptyl, 8-oxa-3-azabicyclo[3.2.1]octyl,3,8-diazabicyclo[3.2.1]octyl, 3,9-diazabicyclo[3.3.1]nonyl and2-oxa-7-azaspiro[3.5]nonyl groups, each of which has a binding site atany possible position. Of these, piperazinyl, pyrrolidinyl andmorpholinyl, each of which has a binding site at any possible position,are preferable as the “heterocycloalkyl group” according to the presentinvention.

In the formulas (1) and (1a), the “arylalkyl group”, the“cycloalkylalkyl group” or the “heterocycloalkylalkyl group” refers to agroup (a group represented by -Ak¹-Ar¹) in which an aryl group, acycloalkyl group or a heterocycloalkyl group (represented by theformula: —Ar¹) as defined herein is bonded at a binding site at anypossible position to a binding site at any possible position in an alkylgroup (represented by the formula: -Ak¹) as defined herein. Of these,“aryl C₁₋₆ alkyl groups (aryl C₁₋₆ alkylene groups)” in which the alkylgroup has 1 to 6 carbon atoms are preferable, and “aryl C₁₋₃ alkylgroups (aryl C₁₋₃ alkylene groups)” in which the alkyl group has 1 to 3carbon atoms are preferable, as the “arylalkyl group” according to thepresent invention. The “cycloalkylalkyl group” according to the presentinvention is preferably a “cycloalkyl C₁₋₆ alkyl group (cycloalkyl C₁₋₆alkylene group)” in which the alkyl group has 1 to 6 carbon atoms; morepreferably a “cycloalkyl C₁₋₃ alkyl group (cycloalkyl C₁₋₃ alkylenegroup)” in which the alkyl group has 1 to 3 carbon atoms; preferably a“C₃₋₆ cycloalkyl C₁₋₆ alkyl group (C₃₋₆ cycloalkyl C₁₋₆ alkylene group)”or a “C₃₋₆ cycloalkyl C₁₋₃ alkyl group (C₃₋₆ cycloalkyl C₁₋₃ alkylenegroup)” in which the cycloalkyl group has 3 to 6 carbon atoms. Further,the “heterocycloalkylalkyl group” according to the present invention ispreferably a “heterocycloalkyl C₁₋₆ alkyl group (heterocycloalkyl C₁₋₆alkylene group)” in which the alkyl group has 1 to 6 carbon atoms; morepreferably a “heterocycloalkyl C₁₋₃ alkyl group (heterocycloalkyl C₁₋₃alkylene group)” in which the alkyl group has 1 to 3 carbon atoms.

Further, in the present invention, the “cyclic amine” refers to anitrogen-containing heterocycle having 3 to 8 atoms, and thenitrogen-containing heterocycle may be a monocyclic ring, or may form afused ring, a crosslinked ring or a spiro ring. Examples of the cyclicamine include, but are not particularly limited to, azetidine,pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine,pyrazole, imidazole, triazole, azepane and azocane. Of these,pyrrolidine, piperidine, piperazine and morpholine are preferable as the“cyclic amine” according to the present invention.

In the present invention, the term “optionally substituted” means thatunless otherwise specified, any hydrogen atom bonded to a groupdescribed as being optionally substituted is substituted with asubstituent (atom or group) selected from the group consisting of otheratoms or groups, and the number of positions at which the hydrogen atomis substituted may be 1 or 2 or more. When the number of positions atwhich the hydrogen atom is substituted is 2 or more, the substituentsare the same or different.

In the present invention, examples of the substituents includesubstituents such as halogen atoms (fluorine atom, chlorine atom,bromine atom and iodine atom), a cyano group, a hydroxyl group, a thiolgroup, a nitro group, C₁₋₆ alkyl groups (preferably C₁₋₃ alkyl groups),aryl groups, heteroaryl groups, cycloalkyl groups (preferably C₃₋₆cycloalkyl groups), heterocycloalkyl groups, arylalkyl groups(preferably aryl C₁₋₃ alkyl groups), heteroarylalkyl groups (preferablyheteroaryl C₁₋₃ alkyl groups), cycloalkylalkyl groups (preferably C₃₋₆cycloalkyl C₁₋₃ alkyl groups), heterocycloalkylalkyl groups (preferablyheterocycloalkyl C₁₋₃ alkyl groups); groups represented by the formula:—N(R^(133a))—R^(133b) [where R^(133a) and R^(133b) are eachindependently a hydrogen atom, a C₁₋₆ alkyl group (preferably a C₁₋₃alkyl group), a cycloalkyl group (preferably a C₃₋₆ cycloalkyl group),an aryl group, a heteroaryl group, or a group represented by theformula: —C(═O)—R^(133c) [where R^(133c) represents a C₁₋₆ alkyl group(preferably a C₁₋₃ alkyl group), a cycloalkyl group (preferably a C₃₋₆cycloalkyl group), an aryl group or a heteroaryl group], or R^(133a) andR^(133b) are linked together to form a four- to seven-membered ringcyclic amine]; groups represented by the formula: —R¹³⁴—C(═O)—R¹³⁵[where R¹³⁴ represents a single bond or an alkylene group having 1 to 3carbon atoms, and R¹³⁵ represents a hydrogen atom, a C₁₋₆ alkyl group(preferably a C₁₋₃ alkyl group), a cycloalkyl group (preferably a C₃₋₆cycloalkyl group), an aryl group or a heteroaryl group]; groupsrepresented by the formula: —R¹³⁶—C(═O)—O—R¹³⁷ [where R¹³⁶ represents asingle bond or an alkylene group having 1 to 3 carbon atoms, and R¹³⁷represents a hydrogen atom, a C₁₋₆ alkyl group (preferably a C₁₋₃ alkylgroup), a cycloalkyl group (preferably a C₃₋₆ cycloalkyl group), an arylgroup or a heteroaryl group]; and groups represented by the formula:—OR¹³⁸ [where R¹³⁸ represents a C₁₋₆ alkyl group (preferably a C₁₋₃alkyl group), a cycloalkyl group (preferably a C₃₋₆ cycloalkyl group), aheterocycloalkyl group, an aryl group, a heteroaryl group, acycloalkylalkyl group (preferably a C₃₋₆ cycloalkyl C₁₋₃ alkyl group), aheterocycloalkylalkyl group (preferably a heterocycloalkyl C₁₋₃ alkylgroup), an arylalkyl group (preferably an aryl C₁₋₃ alkyl group) or aheteroarylalkyl group (preferably a heteroaryl C₁₋₃ alkyl group)]. Ofthe substituents and groups involved in formation of the substituents,alkyl groups, aryl groups, heteroaryl groups, cycloalkyl groups andheterocycloalkyl groups may be further substituted with any substituentas in the definition described above.

Among them, when the group substituted is an aryl group or a heteroarylgroup which is represented by R¹⁰², the substituent is particularlypreferably a halogen atom, a cyano group, a hydroxyl group, anoptionally substituted piperazinyl group (more preferably a piperazinylgroup optionally substituted with a C₁₋₆ alkyl group), an piperazinylC₁₋₆ alkyl group such as a piperazinylmethyl group which is optionallysubstituted (more preferably a piperazinyl C₁₋₆ alkyl group such as apiperazinylmethyl group which is optionally substituted with a C₁₋₆alkyl group), a morpholinyl group; a group represented by the formula:—N(R^(133a))—R^(133b) [where preferably, R^(133a) and R^(133b) eachindependently represent a hydrogen atom or a C₁₋₃ alkyl group]; or agroup represented by the formula: —R¹³⁶—C(═O)—O—R¹³⁷ [where preferably,R¹³⁶ represents an alkylene group having 1 to 3 carbon atoms and R¹³⁷represents a hydrogen atom or a C₁₋₃ alkyl group].

When the group substituted is an arylalkylene group which is representedby R¹¹³; or an alkyl group, an aryl group or a heteroaryl group which isrepresented by R¹¹³ or R¹²², the substituent is particularly preferablya halogen atom, a hydroxyl group, a C₁₋₃ alkyl group; a grouprepresented by the formula: —N(R^(133a))—R^(133b) [where preferably,R^(133a) and R^(133b) each independently represent a hydrogen atom or aC₁₋₃ alkyl group]; or a group represented by the formula: —OR¹³ [wherepreferably, R¹³ represents a C₁₋₃ alkyl group].

When the group substituted is an alkyl group, an aryl group or aheteroaryl group which is represented by R¹¹⁵ or R¹¹⁶, the substituentis particularly preferably a halogen atom, a hydroxyl group, a C₁₋₃alkyl group; a group represented by the formula: —N(R^(133a))—R^(133b)[where preferably, R^(133a) and R^(133b) each independently represent ahydrogen atom or a C₁₋₃ alkyl group]; or a group represented by theformula: —OR¹³⁸ [where preferably, R¹³⁸ represents a C₁₋₃ alkyl group].

When the group substituted is an alkyl group, an aryl group, anarylalkylene group or a heteroaryl group which is represented by R¹²¹,R^(123a) or R^(123b), the substituent is particularly preferably ahalogen atom, a hydroxyl group, a C₁₋₃ alkyl group; a group representedby the formula: —N(R^(133a))—R^(133b) [where preferably, R^(133a) andR^(133b) each independently represent a hydrogen atom or C₁₋₃ alkylgroup]; or a group represented by the formula: —OR¹³⁸ [where preferably,R¹³⁸ represents a C₁₋₃ alkyl group].

In the formulas (1) and (1a), r represents the number of R¹⁰¹, and is 0to 4. r is preferably 0 (i.e. all the four groups corresponding to R¹⁰¹are hydrogen atoms), or 1 or 2. The position of R¹⁰¹ is preferably the7-position or the 8-position when r is 1 or 2.

In the formulas (1) and (1a), each R¹⁰¹ is the same or different when ris 2 or more, and represents a C₁₋₆ alkyl group optionally substitutedwith a halogen atom, OR¹¹¹, or a group represented by the formula:—N(R^(112a))—R^(112b). Here, R¹¹¹, R^(112a) and R^(112b) are eachindependently a hydrogen atom or a C₁₋₆ alkyl group.

R¹⁰¹ is preferably an unsubstituted C₁₋₆ alkyl group; a C₁₋₆ alkyl groupsubstituted with a halogen atom; or OR¹¹ in which R¹¹¹ is a hydrogenatom or a C₁₋₃ alkyl group. More specifically, R¹⁰¹ is more preferably amethyl group, an ethyl group, a hydroxyl group or a trifluoromethylgroup.

In the formulas (1) and (1a), s represents the number of R¹⁰², and is 0to 5. s is preferably 0 (i.e. all the five groups corresponding to R¹⁰²are hydrogen atoms), or 1 to 3. The position of R⁰² is preferably them-position and/or the p-position when r is 1 to 3. The position of R¹⁰is preferably the p-position when r is 1.

In the formulas (1) and (1a), each R¹⁰² is the same or different when sis 2 or more, and represents a halogen atom, OR¹¹³, a group representedby the formula: —N(R^(114a))—R^(114b), a group represented by theformula: —NH—C(═O)—R¹¹⁵, a group represented by the formula:—C(═O)—R¹¹⁶, an optionally substituted aryl group, an optionallysubstituted heteroaryl group, a nitro group or a cyano group.

Here, R¹¹³ is a hydrogen atom, an optionally substituted alkyl group, anoptionally substituted aryl group, an optionally substituted arylalkylgroup, or an optionally substituted heteroaryl group; R^(114a) andR^(114b) each are independently a hydrogen atom or a C₁₋₆ alkyl group;R¹¹⁵ is an optionally substituted alkyl group, an optionally substitutedaryl group, an optionally substituted heteroaryl group, or a grouprepresented by the formula: —NH—R¹²¹; and R¹¹⁶ is an optionallysubstituted alkyl group, an optionally substituted aryl group, anoptionally substituted heteroaryl group, OR¹²², or a group representedby the formula: —N(R^(123a))—R^(123b).

Further, R¹²¹ is an optionally substituted alkyl group, an optionallysubstituted aryl group, or an optionally substituted heteroaryl group;R¹²² is a hydrogen atom, an optionally substituted alkyl group, anoptionally substituted aryl group, or an optionally substitutedheteroaryl group; and R¹²³³ and R^(123b) are each independently ahydrogen atom, an optionally substituted alkyl group, an optionallysubstituted aryl group, or an optionally substituted heteroaryl group,or R^(123a) and R^(123b) are linked together to form a cyclic amine.

R¹⁰² is preferably a halogen atom; OR¹¹³ in which R¹¹³ is an optionallysubstituted alkyl group, an optionally substituted aryl group or anoptionally substituted arylalkyl group; a group represented by theformula: —N(R^(114a))—R^(114b) in which R^(114d) and R^(114b) are eachindependently a hydrogen atom or a C₁₋₃ alkyl group; a group representedby the formula: —C(═O)—R¹⁶ in which R¹¹⁶ is OR¹²²; an optionallysubstituted aryl group; an optionally substituted heteroaryl group; anitro group; or a cyano group, preferably a halogen atom; OR¹¹³ in whichR¹¹³ is an optionally substituted alkyl group; an optionally substitutedaryl group; or an optionally substituted heteroaryl group. Morespecifically, R¹⁰² is more preferably a halogen atom; a methoxy group;an ethoxy group; or a phenyl group optionally substituted with ahydroxyl group, a 4-methylpiperazin-1-yl group, a(4-methylpiperazin-1-yl)methyl group, a 4-morpholin-4-yl group or adimethylamino group.

In the formulas (1) and (1a), R¹⁰³ is a hydrogen atom, a C₁₋₆ alkylgroup, a C₃₋₆ cycloalkyl group, or a C₃₋₆ cycloalkyl C₁₋₆ alkyl group.

R¹⁰³ is preferably a hydrogen atom, a C₁₋₃ alkyl group, C₃₋₆ cycloalkylC₁₋₃ alkyl group. More specifically, R¹⁰³ is more preferably a hydrogenatom, a methyl group, or a cyclopropylmethyl group.

In the formulas (1) and (1a), when R¹⁰¹ is present at the 8-position,R¹⁰¹ and R¹⁰³ present at the 1-position are optionally linked togetherto form a five- to seven-membered ring hetero ring. The five- toseven-membered ring hetero ring is preferably pyrrolidinyl, piperidinylor morpholinyl, more preferably pyrrolidinyl or morpholinyl.

Compounds of the formula (1a) do not include compounds of the formula(1) in which J¹ represents CH, J² represents N, r is 0, R¹⁰³ is ahydrogen atom or a methyl group, R¹⁰ is present at the p-position, andR¹⁰² is a methoxy group. Such compounds of the formula (1a) and saltsthereof are novel dihydroquinazolinone-based compounds.

Examples of preferred aspects of compounds of the formula (1) and (1a)according to the present invention include, but are not limited to, thefollowing aspects (I) to (III), and combinations of two or three of theaspects.

(I) A compound of the above formula (1) or (1a) in which r is 0; or r is1, R¹⁰¹ is present at the 7-position or the 8-position, and R¹⁰¹represents a C₁₋₃ alkyl group optionally substituted with a halogen atomor a hydroxy group; or r is 1, R¹⁰¹ is present at the 8-position, andR¹⁰¹ and R¹⁰³ are linked together to form a five- or six-membered ringhetero ring.

(II) A compound of the above formula (1) or (1a) in which R¹⁰³represents a hydrogen atom, a C₁₋₃ alkyl group or a C₃₋₆ cycloalkyl C₁₋₃alkyl group; or r is 1, R¹⁰¹ is present at the 8-position, and R¹⁰¹ andR¹⁰³ are linked together to form a five- or six-membered ring heteroring.

(III) A compound of the above formula (1) or (1a) in which s is 0; or Sis 1 and R¹⁰² is a halogen atom, OR¹¹³ in which R¹¹³ is an optionallysubstituted C₁₋₃ alkyl group, or an optionally substituted aryl group.

The compounds of the formula (1) and the compounds of the formula (1a)according to the present invention include compounds having microtubuleinhibitory activity. Examples the compounds having microtubuleinhibitory activity include compounds of the above formulas (1) and (1a)in which each of J¹ and J² is N. Examples thereof include compounds inwhich r is 1, R¹⁰¹ is present at the 8-position, and R¹⁰³ is a hydrogenatom; and compounds in which r is 1, R¹⁰¹ is present at the 8-position,and R¹⁰¹ and R⁰³ are linked together to form a five- or six-memberedring hetero ring.

Examples of the compounds of the formula (1) according to the presentinvention include compounds of Examples 1 to 87 shown below, andexamples of the compounds of the formula (1a) according to the presentinvention include compounds of Examples 1 to 81 and 84 to 87 shownbelow.

In the present invention, the term “pharmacologically acceptable” meansbeing suitable for pharmacological use, and pharmacologically acceptablesalts according to the present invention include, but are notparticularly limited to, salts of alkali metals or alkali earth metalssuch as sodium, potassium and calcium; salts of hydrohalic acids such ashydrofluoric acid, hydrochloric acid, hydrobromic acid and hydroiodicacid; salts of inorganic acids such as sulfuric acid, nitric acid,phosphoric acid, perchloric acid and carbonic acid; salts of organiccarboxylic acids such as formic acid, acetic acid, trifluoroacetic acid,trichloroacetic acid, hydroxyacetic acid, propionic acid, lactic acid,citric acid, tartaric acid, oxalic acid, benzoic acid, mandelic acid,butyric acid, fumaric acid, succinic acid, maleic acid and malic acid;salts of acidic amino acids such as aspartic acid and glutamic acid;salts of sulfonic acids such as methanesulfonic acid, ethanesulfonicacid, benzenesulfonic acid and toluenesulfonic acid; and solvates suchas hydrates and alcoholates.

The compounds of the above formulas (1) and (1a) and salts thereof mayhave one or more asymmetric carbon atoms depending on the types ofsubstituents and the like, and optically active substances, enantiomers,any mixtures thereof, racemates and the like based on the one or moreasymmetric carbon atoms are all within the scope of the presentinvention. The group having an unsaturated double bond can be present ina cis- or trans-form. Further, the compounds of the above formulas (1)and (1a) and salts thereof express a form of one of possible isomers(rotational isomers, atropisomers and tautomers) in addition to theabove-described isomers, and these isomers may be present singly, orpresent as a mixture thereof. Herein, a compound which has any of theabove-described isomers and isotopes and whose name is not particularlyspecified may be one of the isomers and isotopes, or a mixture or aracemate of two or more of the isomers and isotopes.

The compounds of the formulas (1) and (1a) and pharmacologicallyacceptable salts thereof according to the present invention(hereinafter, sometimes referred to as “dihydroquinazolinone-basedcompounds”) can be produced through the methods shown below. The methodfor producing a dihydroquinazolinone-based compound according to thepresent invention is not limited to the methods shown below, and a scopeof the compounds according to the present invention is not limited tocompounds produced by the following production methods.

The method for producing a dihydroquinazolinone-based compound accordingto the present invention can be carried out by combining a wide range ofvarious kinds of synthesis methods known to persons skilled in the art,methods obtained by making a modification or the like to the synthesismethods if necessary, and the like while using starting raw materials,precursors, reagents and solvents which are commercially available orcan be synthesized through methods known to persons skilled in the art.

A method for introducing, modifying or converting any substituent or thelike can be carried out by introducing, modifying or converting anintended substituent itself or a group convertible to the substituent ina raw material stage, an intermediate material stage or a final-formmaterial stage by combining a wide range of various kinds of synthesismethods known to persons skilled in the art, methods obtained by makinga modification or the like to the synthesis methods if necessary, andthe like. The method can also be carried out by appropriately changingthe order of reaction steps, etc. The method can also be carried out byappropriately employing general means such as protection anddeprotection of functional groups which are commonly used in organicsynthesis chemistry if necessary for convenience of the reaction (e.g.,methods described in, for example, Green Wuts, PROTECTIVE GROUPS inORGANIC SYNTHESIS THIRD EDITION, John Wiley & Sons, Inc.).

Reaction apparatuses usable in production of the compound include commonglass reaction vessels, optionally glass-lined metallic reaction baths,and flow reactors. Examples of cooling or heating at the time ofcarrying out the reaction include air cooling, water cooling, icecooling, combination of a cryogen and a cooling medium, and cooling of areaction vessel or a reaction mixture through a cooling medium cooled bya freezing machine, or heating with hot water or steam, heating of areaction vessel directly by an electric heater or through a heatingmedium, and heating by application of an ultrashort electromagnetic wave(i.e. microwave heating). Further, cooling or heating using a Peltierdevice, etc. can also be performed.

The dihydroquinazolinone-based compound according to the presentinvention can be prepared through, for example, the following method.

(Production Method)

In the above formulas (2) and (3), J¹, J², r, R¹⁰¹, s, R¹⁰² and R¹⁰³ areeach independently the same as J¹, J², r, R¹⁰¹, s, R¹⁰² and R¹⁰³ in theabove formula (1) or (1a), respectively.

The compound of the formula (2) (hereinafter, referred to as a “rawmaterial (2)” and the compound of the formula (3) (hereinafter, referredto as a “raw material (3)”) in the above production method can beobtained as commercially available reagents, or can be synthesizedthrough known methods or methods based on the known methods.

In the above production method according to the present invention, theraw material (2) and the raw material (3) are dissolved or suspended inan appropriate solvent, and reacted in the presence or non-presence ofan acid catalyst to produce a dihydroquinazolinone-based compoundaccording to the present invention (a compound of the formula (1) or asalt thereof, or a compound of the formula (1a) or a salt thereof, whichis hereinafter sometimes referred to as a “compound (1)” or a “compound(1a)”).

In the above production method, the raw material (2) and the rawmaterial (3) are used normally at a molar ratio in the range of 1:1 to3, preferably at a molar ratio in the range of 1:1 to 1.2.

Examples of the solvent to be used in the above production methodinclude protic solvents such as water, methanol, ethanol, n-propanol,2-propanol, n-butanol, 2-butanol and tert-butyl alcohol;hydrocarbon-based solvents such as petroleum ether, n-pentane, n-hexane,n-heptane, cyclohexane, benzene, toluene and xylene; halogen-basedsolvents such as carbon tetrachloride, dichloromethane, chloroform,1,2-dichloroethane, chlorobenzene and trifluoromethylbenzene;ether-based solvents such as diethyl ether, diisopropyl ether, methyltert-butyl ether, methyl cyclopentyl ether, tetrahydrofuran,2-methyltetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and diphenylether; ester-based solvents such as methyl acetate, ethyl acetate,n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate,tert-butyl acetate, benzyl acetate, methyl propionate, ethyl propionate,n-propyl propionate, isopropyl propionate, n-butyl propionate, isobutylpropionate and tert-butyl propionate; and aprotic polar solvents such asacetone, 2-butanone, methylisobutylketone, cyclohexanone, acetonitrile,propionitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide and N-methyl-2-pyrrolidone. One of these solvents can be usedalone, or two or more thereof can be mixed at an appropriate ratio andused. Of these, at least one of methanol, ethanol, n-propanol andN,N-dimethylformamide is preferably used as the solvent.

Examples of the acid to be used at the time of carrying out the reactionin the presence of the acid catalyst in the above production methodinclude mineral acids such as hydrochloric acid, hydrobromic acid,hydroiodic acid, sulfuric acid, phosphoric acid and nitric acid;carboxylic acids such as formic acid, acetic acid, propionic acid andtrifluoroacetic acid; and Lewis acids such as boron trifluoride-diethylether complexes, boron trichloride, boron tribromide, zinc chloride,stannic chloride, ferric chloride, aluminum chloride, titaniumtetrachloride and zirconium tetrachloride. Of these, at least one ofhydrochloric acid, formic acid, acetic acid and propionic acid ispreferable, with acetic acid being more preferable, as the acid. Theamount of the acid used is in the range of 0.01 to 20 equivalents,preferably in the range of 0.05 to 5 equivalents, more preferably in therange of 0.1 to 1 equivalents, based on the amount of the raw material(2). Alternatively, the amount is in the range of 0.01 to 20equivalents, preferably in the range of 0.1 to 10 equivalents, morepreferably in the range of 1 to 5 equivalents.

In the above production method, the reaction temperature is in the rangeof 0 to 250° C., preferably 30 to 200° C., more preferably 60 to 160° C.In the above production method, the reaction time is in the range of 1minute to 2 days, preferably 5 minutes to 12 hours, more preferably 10minutes to 6 hours.

In the above production method, optional substituents with which R¹⁰² issubstituted may have intended substituents in the stage of the rawmaterial (3). In this case, the resulting compound (1) or compound (1a)has the intended substituents. By introducing, modifying or convertingprecursor groups for intended substituents in the raw material (3) bycombining a wide range of various kinds of synthesis methods known topersons skilled in the art, the compound (1) or compound (1a) having theintended substituents can be produced. These synthesis methods can bearbitrarily combined, and protection, deprotection and the like may beappropriately performed if necessary.

The raw material (3) in the production method according to the presentinvention can be produced through, for example, methods shown in thefollowing schemes 1 and 2.

In the above formulas (4), (5) and (3-1), s and R¹⁰² are eachindependently the same as s and R¹⁰² in the above formula (1) or (1a),respectively.

The compound of the formula (4) (hereinafter, referred to as a “rawmaterial (4)”) in the scheme 1 can be obtained as a commerciallyavailable reagent, or can be synthesized through a known method or amethod based on the known method.

The compound of the formula (3-1) (hereinafter, referred to as a “rawmaterial (3-1)”) in the scheme 1 is a type of raw material (3). By usinga known method such as the method described in Synthesis, 1998, 10,1140., the raw material (3-1) can be produced from the compound of theformula (5) (compound (5)) which can be synthesized through acondensation reaction of the raw material (4) and semicarbazidehydrochloride. A series of all these synthesis methods are based onmethodologies extensively described in general documents of organicchemistry, and the syntheses can be performed through the describedmethods themselves or modifications thereof.

In the above formulas (6), (7), (8), (9) and (3-2), s and R¹⁰² are eachindependently the same as s and R¹⁰² in the above formula (1) or (1a),respectively.

The compound of the formula (6) (hereinafter, referred to as a “rawmaterial (6)”) and the compound of the formula (9) (hereinafter,referred to as a “raw material (9)”) in the scheme 2 can be obtained ascommercially available reagents, or can be synthesized through knownmethods or methods based on the known methods.

The compound of the formula (3-2) (hereinafter, referred to as a “rawmaterial (3-2)” in the scheme 2 is a type of raw material (3). The rawmaterial (3-2) can be synthesized by adding sodium azide to the compoundof the formula (8) (compound (8)) (step C: Tetrahedron Letters, 2001,42, 9117.), and the compound (8) can be synthesized in two steps (step Aand step B) from the raw material (6) or in one step (step D) from theraw material (9) (steps A and B: method described in Bioorganic &Medicinal Chemistry Letters, 2008, 184932., etc.; and step D: methoddescribed in Tetrahedron Letters, 2001, 42, 9117., etc.). A series ofall these synthesis methods are based on methodologies extensivelydescribed in general documents of organic chemistry, and the synthesescan be performed through the described methods themselves ormodifications thereof.

The dihydroquinazolinone-based compound synthesized through the aboveproduction method, the intermediate, the raw material and the like maybe used in the next step in a state of a reaction solution or a crudeproduct, or used after being isolated through a common purificationmethod known to persons skilled in the art. Examples of the purificationmethod associated with isolation include methods obtained byappropriately selecting or combining various types of chromatography(column or thin-layer and normal phase or reversed phase chromatography;gel permeation chromatography (GPC) and the like), distillation,sublimation, precipitation, crystallization and centrifugation.

The dihydroquinazolinone-based compounds of the present invention,tautomers and stereoisomers thereof, and mixtures of these compounds atany ratios have an excellent tankyrase inhibitory action and/ormicrotubule inhibitory action, and thus can be administered alone or incombination with at least one of conventionally known methods fortreating a disease including conventional operative treatments,radiation treatments and anticancer agent treatments in treatment ofdiseases such as various solid tumors and blood tumors as diseasesattributable to tankyrase and/or microtubules or intracellular molecularreactions related to the tankyrase and/or microtubules (e.g.,fibrosarcoma, ovary cancer, glioblastoma, pancreatic cancer, breastcancer, astrocytoma, lung cancer, gastric cancer, liver cancer,colorectal cancer, bladder cancer and leukemia); infections such asHerpes simplex virus infection and Epstein-Barr virus infection;fibroses such as pulmonary fibrosis; neurodegenerative diseases such ascherubism, multiple sclerosis and amyotrophic lateral sclerosis; varioustypes of inflammatory diseases such as skin and cartilage damages; andmetabolic diseases such as obesity.

The cell proliferation inhibitor of the present invention contains thedihydroquinazolinone-based compound of the present invention as anactive ingredient. Therefore, the cell proliferation inhibitor of thepresent invention can be used as a tankyrase inhibitor, a microtubuleinhibitor (preferably a microtubule polymerization inhibitor or amicrotubule depolymerization inhibitor, more preferably a microtubulepolymerization inhibitor), or a pharmaceutical composition (morespecifically a prophylactic or therapeutic agent for a diseaseattributable to tankyrase and/or microtubules), and such an agent can beused as a proliferation suppressive agent or a prophylactic ortherapeutic agent for the solid tumors and blood tumors; or aprophylactic or therapeutic agent for the infections, pulmonaryfibroses, multiple sclerosis or amyotrophic lateral sclerosis.

In the present invention, the cell proliferation inhibitors include cellproliferation inhibitors in a broad sense, i.e. cell proliferationinhibitors for direct suppression of proliferation of cells of the solidtumors, blood tumors and the like, suppression of invasion andmetastasis of the cells, and suppression of tumor angiogenesis, and thecell proliferation inhibitor refers to an agent for suppression,prevention or retardation of proliferation and metastasis of the cells.

The cell proliferation inhibitor of the present invention may furthercontain therapeutic agents other than the dihydroquinazolinone-basedcompound of the present invention, or may be used in combination withother therapeutic agents simultaneously or intertemporally. Examples ofthe other therapeutic agents include other anticancer agents(antiproliferative agents, antineoplastic agents, DNA-damaging agentsand combinations thereof). More specifically, alkylating agents (e.g.,temozolomide and melphalan); antimetabolites (e.g., gemcitabine,cytarabine (Ara-C), fluorouracil (5-FU), pemetrexed, mercaptopurine andmethotrexate); plant alkaloids (e.g., irinotecan (SN-38) and etoposide(VP-16)); anticancer antibiotics (e.g., actinomycin D, daunorubicin,doxorubicin, bleomycin and mitoxantrone); platinating agents (e.g.,oxaliplatin, carboplatin and cisplatin); other microtubule inhibitors(e.g., paclitaxel, vinblastine, vincristine, vindesine, vinorelbine,docetaxel, cabazitaxel, eribulin and pharmacologically acceptable saltsthereof); mitosis inhibitors; topoisomerase inhibitors; cell divisioninhibitors; growth factor function inhibitors such as EGFR antibodies;angiogenesis inhibition agonists such as VEGFR antibodies; cancer cellmetastasis suppression agonists such as metalloprotease inhibitors;antisense therapeutic drugs such as Ras antisense; and immunotherapeuticdrugs with anti-PD-1 antibodies and T-cells. One of these therapeuticagents may be used alone, or two or more thereof may be used incombination.

The cell proliferation inhibitor of the present invention may beadministered through any of oral and parenteral administration routssuch as routs of inhalation administration, nasal administration,ophthalmic administration, subcutaneous administration, intravenousadministration, intramuscular administration, rectal administration andtransdermal administration, and can be administered to humans or animalsother than humans. Therefore, the cell proliferation inhibitor of thepresent invention may take an appropriate dosage form depending on anadministration route.

Specific examples of the dosage form of the cell proliferation inhibitorof the present invention include oral agents such as tablets, pills,capsules, granules, powders, fine granules, troches, elixirs,suspensions, emulsions and syrups; solutions for external use such asinhalations, nasal solutions and ophthalmic solutions; injections suchas intravenous injections and intramuscular injections; and parenteralagents such as rectal administration agents, suppositories, lotions,sprays, ointments, creams and patches.

The cell proliferation inhibitor of the present invention may furthercontain, depending on the dosage form, excipients such as diluents,extenders, humectants, surfactants, disintegrants, binders, lubricatingagents, dispersants, buffering agents, preservatives, solubilizingagents, antiseptics, correctives, soothing agents, stabilizers,lubricants and colorants which are commonly used in the area ofpharmaceuticals. Production can be performed through conventionalmethods using these additives. Examples of the additives includelactose, fructose, glucose, starch, gelatin, magnesium carbonate,synthetic magnesium silicate, talc, magnesium stearate, methylcellulose,carboxymethylcellulose or salts thereof, gum arabic, olive oil,propylene glycol, polyethylene glycol, syrup, vaseline, glycerin,ethanol, citric acid, sodium chloride, sodium sulfite and sodiumphosphate.

In cell proliferation inhibitor of the present invention, the content ofthe dihydroquinazolinone-based compound of the present invention (in thecase where the dihydroquinazolinone-based compound is a mixture of acompound of the above formula (1) or (1a), a pharmacologicallyacceptable salt thereof, a tautomer and a stereoisomer thereof, and thelike, the total content of these components is regarded as the contentof the dihydroquinazolinone-based compound) is appropriately adjusteddepending on a dosage form of the agent, and therefore may vary, and thecontent of the dihydroquinazolinone-based compound is typically 0.01 to70 mass %, preferably 0.05 to 50 mass %, in terms of a free form, basedon the total mass of the cell proliferation inhibitor. The dosage of thedihydroquinazolinone-based compound of the present invention (in thecase where the dihydroquinazolinone-based compound is a mixture of acompound of the above formula (1) or (1a), a pharmacologicallyacceptable salt thereof, a tautomer and a stereoisomer thereof, and thelike, the total amount of these components is regarded as the amount ofthe dihydroquinazolinone-based compound) is appropriately adjusteddepending on an individual case with consideration given to the doseregimen and the age, the body weight, the sex, the type of disease andthe severity of a symptom of a patient, and the like, and therefore mayvary, and the dosage of the dihydroquinazolinone-based compound istypically 0.1 to 2,000 mg, preferably 1 to 1,000 mg, in terms of a freeform, per day per adult. This amount of the dihydroquinazolinone-basedcompound is administered once or in several divided doses a day.

EXAMPLES

Hereinafter, the present invention will be described in more detail onthe basis of Examples, which should not be construed as limiting thescope of the present invention. Various applications, changes,modifications and the like can be made without departing from the scopeof the present invention. Further, methods for producing intermediatesand raw materials used in Examples will be described in ReferenceExamples, which are examples shown for explaining implementation of thepresent invention in detail, and are should not be construed as limitingthe scope of the present invention. Various applications, changes,modifications and the like can be made without departing from the scopeof the present invention.

Abbreviations used in Examples and Reference Examples below have thefollowing meanings.

M: mol/L

¹H-NMR: proton nuclear magnetic resonance spectrum (270 MHz or 500 MHz)

MS (ESI): mass spectrum (electrospray ionization method)

DMSO: dimethyl sulfoxide

Bn: benzyl

TFA: trifluoroacetic acid

Reference Example 1 Methyl 4-(4-formyl-1H-pyrazol-3-yl)benzoate

<Step 1>

Methyl 4-acetylbenzoate (2.08 g) was suspended in methanol (40 mL). Tothis, an aqueous solution (40 mL) of sodium acetate (1.24 g) andsemicarbazide hydrochloride (1.43 g) was added. The mixture was refluxedunder heating for 5 hours, and allowed to cool to room temperature,water (20 mL) was then added, and the mixture was stirred for severalminutes. The precipitated solid was taken by filtration, washed with 100mL of water, and then air-dried to give methyl(E)-4-(1-2-carbamoylhydrazono)ethylbenzoate (2.66 g) as a white solid.

MS(ESI) m/z: 236.12 [M+H]⁺

<Step 2>

Methyl (E)-4-(1-2-carbamoylhydrazono)ethylbenzoate (5.05 g) wasdissolved in N,N-dimethylformamide (50 mL), and the solution was cooledin an ice bath. Phosphorus oxychloride (17.5 mL) was added dropwisewhile an internal temperature of 5 to 10° C. was maintained. The mixturewas stirred at 5° C. for 30 minutes, then heated to an internaltemperature of 65° C., stirred for 4.5 hours, and cooled to roomtemperature. Thereafter, the reaction mixture was added little by littleto ice water (200 mL) to terminate the reaction. A 25% sodium hydroxideaqueous solution was added dropwise to adjust the pH to 7.0. Theprecipitated solid was taken by filtration, washed with water (30 mL×3),and then dried by heating under reduced pressure (50° C.) to give thetitle compound (3.80 g) as a light brown solid.

¹H-NMR (270 MHz, DMSO-d₆) δ: 3.89 (s, 3H), 8.05 (brs, 4H), 8.66 (brs,1H), 9.95 (s, 1H), 13.88 (brs, 1H).

MS (ESI) m/z: 231.12 [M+H]⁺.

Reference Example 25-(4-(2,2,2-Trifluoroethoxy)phenyl)-2H-1,2,3-triazole-4-carbaldehyde

<Step 1>

Carbon tetrabromide (6.5 g) was dissolved in dichloromethane (35 mL),and the solution was cooled to −20° C. To this, a dichloromethanesolution (35 mL) of triphenylphosphine (5.14 g) was added dropwise at−20° C. The mixture was stirred for 1 hour, and a solution obtained bydissolving 4-(2,2,2-trifluoroethoxy)benzaldehyde (2.00 g) andtriethylamine (1.37 mL) in dichloromethane (20 mL) was then addeddropwise at −20° C. The mixture was heated to room temperature, andstirred for 4 hours, and petroleum ether (100 mL) was then addeddropwise. The insoluble matter was separated by filtration, and washedwith a dichloromethane/petroleum ether mixed solvent (1/1). The filtratewas concentrated, and the brown oil thus obtained was purified by silicagel chromatography (hexane/ethyl acetate=100/0 to 90/10) to give1-(2,2-dibromovinyl)-4-(2,2,2-trifluoroethoxy)benzene (2.21 g) as acolorless and transparent oil.

¹H-NMR (270 MHz, CDCl₃) δ: 4.36 (q, J=7.9 Hz, 2H), 6.89-6.98 (m, 2H),7.42 (s, 1H), 7.49-7.58 (m, 2H).

<Step 2>

1-(2,2-Dibromovinyl)-4-(2,2,2-trifluoroethoxy)benzene (2.05 g) wasdissolved in tetrahydrofuran (40 mL), and the solution was cooled to−78° C. A hexane solution of n-butyllithium (1.6 M solution; 7.47 mL)was added dropwise at −78° C., and the mixture was stirred at −78° C.for 2 hours. Subsequently, N,N-dimethylformamide (661 μL) was then addeddropwise at −78° C., and the mixture was then heated to roomtemperature, and stirred for 2.5 hours. The reaction mixture was addeddropwise to a mixed solution of a 10% potassium dihydrogenphosphateaqueous solution (40 mL) and methyl tert-butyl ether (40 mL) toterminate the reaction. The organic layer was separated, washed withwater (80 mL×2), washed with brine (80 mL), dried over magnesiumsulfate, and concentrated. The residue thus obtained was purified bysilica gel column chromatography (hexane/ethyl acetate=100/0 to 70/30)to give 3-(4-(2,2,2-trifluoroethoxy)phenyl)propiolaldehyde (283 mg) as ayellow crystalline solid.

¹H-NMR (270 MHz, DMSO-d₆) δ: 4.40 (q, J=7.9 Hz, 2H), 6.94-7.01 (m, 2H),7.57-7.64 (m, 2H), 9.41 (s, 1H).

<Step 3>

A dimethyl sulfoxide solution (1 mL) of3-(4-(2,2,2-trifluoroethoxy)phenyl)propiolaldehyde (275 mg) was addeddropwise to a dimethyl sulfoxide solution (2.6 mL) of sodium azide (86.2mg) at room temperature, and the reaction mixture was stirred at roomtemperature for 1 hour. The reaction mixture was added dropwise to amixed solution of a 15% potassium dihydrogenphosphate aqueous solution(10 mL) and methyl tert-butyl ether (10 mL) to terminate the reaction.The organic layer was separated, washed with water (10 mL×2), washedwith brine (10 mL), and dried over magnesium sulfate. The solvent wasconcentrated to give the title compound (315 mg) as a light yellowsolid.

¹H-NMR (270 MHz, DMSO-d₆) δ: 4.87 (q, J=8.9 Hz, 2H), 7.20-7.27 (m, 2H),7.96-8.03 (m, 2H), 10.17 (s, 1H).

MS (ESI) m/z: 272.13 [M+H]⁺.

Reference Example 3 5-(4-Propoxyphenyl)-2H-1,2,3-triazole-4-carbaldehyde

<Step 1>

1-Ethynyl-4-propoxybenzene (5.00 g) was dissolved in tetrahydrofuran (35mL), and the solution was cooled to −40° C. A hexane solution ofn-butyllithium (1.6 M solution; 23.4 mL) was added dropwise at −40° C.,and the mixture was stirred at −40° C. for 20 minutes. Subsequently,N,N-dimethylformamide (4.83 mL) was added dropwise at −40° C., and themixture was then heated to room temperature, and stirred for 1 hour. Thereaction mixture was added dropwise to a mixed solution of a 10%potassium dihydrogenphosphate aqueous solution (200 mL) and methyltert-butyl ether (200 mL) to terminate the reaction. The organic layerwas separated, washed with water (100 mL×2), washed with brine (100 mL),dried over magnesium sulfate, and concentrated. The residue thusobtained was purified by silica gel column chromatography (hexane/ethylacetate=100/0 to 90/10) to give 3-(4-propoxyphenyl)propiolaldehyde (4.60g) as a yellow crystalline solid.

¹H-NMR (270 MHz, CDCl₃) δ: 1.04 (t, J=7.4 Hz, 3H), 1.74-1.90 (m, 2H),3.96 (t, J=6.9 Hz, 2H), 6.85-6.93 (m, 2H), 7.49-7.59 (m, 2H), 9.40 (brs,1H).

<Step 2>

The title compound (5.12 g) was prepared from3-(4-propoxyphenyl)propiolaldehyde (4.30 g) in a manner similar to thatof <Step 3> of Reference Example 2.

¹H-NMR (270 MHz, DMSO-d₆) δ: 1.00 (t, J=7.4 Hz, 3H), 1.68-1.84 (m, 2H),4.01 (t, J=6.6 Hz, 2H), 7.06-7.13 (m, 2H), 7.92-7.99 (m, 2H), 10.16 (s,1H).

MS (ESI) m/z: 232.14 [M+H]⁺.

Reference Example 45-(4-(2,2-Difluoroethoxy)phenyl)-2H-1,2,3-triazole-4-carbaldehyde

<Step 1>

5-(4-(Benzyloxy)phenyl)-2H-1,2,3-triazole-4-carbaldehyde (1.16 g) wasprepared from 3-(4-benzyloxy)phenylpropiolaldehyde (1.00 g) in a mannersimilar to that of <Step 3> of Reference Example 2.

¹H-NMR (270 MHz, DMSO-d₆) δ: 5.20 (s, 2H), 7.15-7.22 (m, 2H), 7.31-7.52(m, 5H), 7.92-7.99 (m, 2H), 10.16 (s, 1H).

MS (ESI) m/z: 280.19 [M+H]^(|).

<Step 2>

5-(4-(Benzyloxy)phenyl)-2H-1,2,3-triazole-4-carbaldehyde (200 mg) wasdissolved in tetrahydrofuran (2 mL), 3,4-dihydro-2H-pyran (196 μL) andp-toluenesulfonic acid monohydrate (13.6 mg) were added, and the mixturewas stirred at room temperature for 2.5 hours. The reaction mixture wasdiluted with ethyl acetate (10 mL), and then washed with saturatedsodium bicarbonate water (10 mL), and then with brine (10 mL), and driedover magnesium sulfate. The solvent was concentrated, and the residuethus obtained was purified by silica gel column chromatography(hexane/ethyl acetate=92/8 to 71/29) to give5-(4-(benzyloxy)phenyl-2-(tetrahydro-2H-pyran-2-yl)-2H-1,2,3-triazole-4-carbaldehyde(261 mg) as a white solid.

¹H-NMR (270 MHz, CDCl₃) δ: 1.67-1.84 (m, 3H), 2.09-2.21 (m, 2H),2.39-2.54 (m, 1H), 3.74-3.89 (m, 1H), 4.03-4.13 (m, 1H), 5.13 (s, 2H),5.81 (dd, J=8.6, 2.6 Hz, 1H), 7.03-7.09 (m, 2H), 7.30-7.48 (m, 5H),8.02-8.12 (m, 2H), 10.24 (s, 1H).

<Step 3>

5-(4-(Benzyloxy)phenyl)-2-(tetrahydro-2H-pyran-2-yl)-2H-1,2,3-triazole-4-carbaldehyde(244 mg) was dissolved in tetrahydrofuran (5 mL), 20% palladiumhydroxide-carbon (containing about 50% of water; 50 mg) was added, andthe mixture was vigorously stirred at room temperature for 80 minutes ina hydrogen atmosphere. A mixed solvent (10 mL) of chloroform/methanol(9/1) was added, the mixture was filtered through Celite, and thefiltrate was concentrated. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate=80/20 to 50/50) to give5-(4-hydroxyphenyl)-2-(tetrahydro-2H-pyran-2-yl)-2H-1,2,3-triazole-4-carbaldehyde(147 mg) as a white solid.

¹H-NMR (270 MHz, CDCl₃) δ: 1.65-1.86 (m, 3H), 2.07-2.22 (m, 2H),2.39-2.57 (m, 1H), 3.75-3.87 (m, 1H), 4.03-4.16 (m, 1H), 5.22 (brs, 1H),5.82 (dd, J=8.6, 2.6 Hz, 1H), 6.87-6.97 (m, 2H), 7.99-8.07 (m, 2H),10.24 (s, 1H).

<Step 4>

5-(4-Hydroxyphenyl)-2-(tetrahydro-2H-pyran-2-yl)-2H-1,2,3-triazole-4-carbaldehyde(61.6 mg) was dissolved in N,N-dimethylformamide (2 mL), cesiumcarbonate (147 mg) was added, and the mixture was stirred at roomtemperature for 5 minutes. To this, 1,1-difluoro-2-iodoethane (29.8 μL)was added, and the mixture was stirred at 50° C. for 3 hours, and cooledto room temperature. Thereafter, water (10 mL) and ethyl acetate (10 mL)were added, and the mixture was separated. The aqueous layer wasextracted with ethyl acetate (5 mL). The organic layers were combined,washed with water (10 mL×2), and then with brine (10 mL), dried overmagnesium sulfate, and concentrated. The residue thus obtained waspurified by silica gel column chromatography (hexane/ethyl acetate=90/10to 70/30) to give5-(4-(2,2-difluoroethoxy)phenyl)-2-(tetrahydro-2H-pyran-2-yl)-2H-1,2,3-triazole-4-carbaldehyde(71.5 mg) as a colorless and transparent oil.

¹H-NMR (270 MHz, CDCl₃) δ: 1.66-1.85 (m, 3H), 2.08-2.23 (m, 2H),2.39-2.55 (m, 1H), 3.74-3.87 (m, 1H), 4.06-4.17 Cm, 1H), 4.24 (td,J=13.0, 4.0 Hz, 2H), 5.82 (dd, J=8.6, 2.6 Hz, 1H), 6.12 (tt, J=55.1, 4.1Hz, 1H), 6.97-7.04 (m, 2H), 8.07-8.14 (m, 2H), 10.24 (s, 1H).

<Step 5>

5-(4-(2,2-Difluoroethoxy)phenyl)-2-(tetrahydro-2H-pyran-2-yl)-2H-1,2,3-triazole-4-carbaldehyde(64.1 mg) was dissolved in 1,4-dioxane (1 mL), a 4 M hydrogenchloride/1,4-dioxane solution (1 mL) was added at room temperature, andthe mixture was stirred. After 1 hour, methanol (1 mL) and a 4 Mhydrogen chloride/1,4-dioxane solution (1 mL) were added, and themixture was further stirred for 1 hour. The solvent was concentrated,and the residue was diluted with ethyl acetate (5 mL), and washed withsaturated sodium bicarbonate water (5 mL). The aqueous layer wasextracted with ethyl acetate (5 mL). The organic layers were combined,washed with brine (10 mL), and dried over magnesium sulfate. The solventwas concentrated to give the title compound (31.2 mg) as a white solid.

¹H-NMR (270 MHz, DMSO-d₆) δ: 4.33-4.50 (m, 2H), 6.43 (tt, J=54.4, 3.6Hz, 1H), 7.14-7.24 (m, 2H), 7.94-8.03 (m, 2H), 10.16 (s, 1H).

MS (ESI) m/z: 254.11 [M+H]⁺.

Reference Example 5 3,4-Dihydro-2H-benzo[b][1,4]oxazine-5-carboxamide

3,4-Dihydro-2H-benzo[b][1,4]oxazine-5-carboxylic acid (150 mg) and1-hydroxybenzotriazole (170 mg) were dissolved in N,N-dimethylformamide(1 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (241mg) was added, and the mixture was stirred for 5 minutes. The reactionmixture was cooled with ice, aqueous ammonia (28%; 1 mL) was addeddropwise, and the mixture was then stirred for 1 hour. To this, water (4mL) was added, the mixture was stirred, and the precipitated solid wastaken by filtration. The solid was washed with water, and dried byheating under reduced pressure to give the title compound (98.6 mg) as awhite solid.

¹H-NMR (270 MHz, CDCl₃) δ: 3.51 (td, J=4.5, 2.6 Hz, 2H), 4.22 (t, J=4.0Hz, 2H), 5.72 (brs, 2H), 6.50 (t, J=7.6 Hz, 1H), 6.84-6.90 (m, 1H), 6.98(dd, J=7.9, 1.3 Hz, 1H), 7.64 (brs, 1H).

MS (ESI) m/z: 179.06 [M+H]^(|).

The compounds of Reference Examples 6 to 19 shown in Tables 1 and 2below were prepared using the methods of Reference Examples 1 to 5 andmethods based thereon, and methods disclosed in literatures and methodsbased thereon.

TABLE 1 Reference ¹H NMR (270 MHz) ESI MS Example Compound nameStructural Formula δ ppm Solvent m/z 6 (E)-2-(1-(4- (Benzyloxy)-3-fluorophenyl)eth- ylidene)hydrazine- 1-carboxamide

302.27 [M + H]+ 7 3-(4-(Benzyloxy)- 3-fluorophenyl)- 1H-pyrazole-4-carbaldehyde

5.22 (s, 2 H), 7.05-7.16 (m, 1 H), 7.32-7.55 (m, 7 H), 8.16 (s, 1 H),9.98 (s, 1 H) CDC13 297.23 [M + H]+ 8 (E)-2-(1-(3,5- Difluoro-4-methoxyphenyl)eth- ylidene)hydrazine-1- carboxamide

244.21 [M + H]+ 9 3-(3,5-Difluoro-4- methoxyphenyl)- 1H-pyrazole-4-carbaldehyde

3.99 (s, 3 H), 7.73-7.84 (m, 2 H), 8.55 (s, 1 H), 9.90 (s, 1 H) DMSO-d6239.22 [M + H]+ 10 5-(4- Ethoxyphenyl)- 2H-1,2,3-triazole-4-carbaldehyde

1.36 (t, J = 7.0 Hz, 3 H), 4.11 (q, J = 7.0 Hz, 2 H), 7.09 (d, J = 8.6Hz, 2 H), 7.96 (d, J = 8.6 Hz, 2 H), 10.16 (s, 1 H) DMSO-d6 218.13 [M +H]+ 11 1-(2,2- Dibromovinyl)-4- (difluoro- methoxy)benzene

6.54 (t, J = 72.9 Hz, 1 H), 7.12 (d, J = 8.9 Hz, 2 H), 7.45 (s, 1 H),7.54 (d, J = 8.9 Hz, 2 H) CDCl3 12 3-(4- (Difluoro- methoxy)phe-nyl)propiolaldehyde

6.58 (t, J = 72.5 Hz, 1 H), 7.12-7.20 (m, 2 H), 7.57-7.68 (m, 2 H), 9.42(s, 1 H) CDCl3

TABLE 2 Reference ¹H NMR (270 MHz) ESI MS Example Compound nameStructural Formula δ ppm Solvent m/z 13 5-(4- (Difluoromethoxy)phenyl)-2H-1,2,3- triazole-4- carbaldehyde

7.00-7.72 (m, 3 H), 8.05 (br d, J = 8.6 Hz, 2 H), 10.18 (s, 1 H) DMSO-d6240.08 [M + H]+ 14 3-(4- Isopropoxyphenyl) propiolaldehyde

1.36 (d, J = 6.3 Hz, 6 H), 4.61 (spt, J = 6.0 Hz, 1 H), 6.84-6.92 (m, 2H), 7.50-7.58 (m, 2 H), 9.40 (s, 1 H) CDCl3 15 5-(4- Isopropoxyphenyl)-2H-1,2,3-triazole- 4-carbaldehyde

1.30 (d, J = 5.9 Hz, 6 H), 4.73 (spt, J = 5.9 Hz, 1 H), 7.08 (d, J = 8.9Hz, 2 H), 7.91 (d, J = 8.6 Hz, 2 H), 10.16 (s, 1 H) DMSO-d6 232.14 [M +H]+ 16 3-(4-(Methoxy- d₃)phenyl) propiolaldehyde

6.87-6.95 (m, 2 H), 7.54-7.60 (m, 2 H), 9.40 (s, 1 H) CDCl3 175-(4-(Methoxy- d₃)phenyl)-2H- 1,2,3-triazole-4- carbaldehyde

7.11 (m, J = 8.9 Hz, 2 H), 7.96 (m, J = 8.9 Hz, 2 H). 10.16 (s. 1 H)DMSO-d6 207.15 [M + H]+ 18 Ethyl 2-(4-(5- formyl-2- (tetrahydro-2H-pyran-2-yl)-2H- 1,2,3-triazol-4- yl)phenoxyacetate

1.31 (t, J = 7.3 Hz, 3 H), 1.66-1.86 (m, 3 H), 2.09-2.22 (m, 2 H),2.39-2.55 (m, 1 H), 3.74-3.87 (m, 1 H), 4.04-4.16 (m, 1 H), 4.29 (q, J =7.1 Hz, 2 H), 4.67 (s, 2 H), 5.82 (dd, J = 8.6, 2.6 Hz, 1 H), 6.95- 7.04(m, 2 H), 8.06- 8.13 (m, 2 H), 10.24 (s, 1 H) CDCl3 19 Ethyl 2-(4-(5-formyl-2H-1,2,3- triazol-4- yl)phenoxyacetate

1.23 (t, J = 7.0 Hz, 3 H), 4.19 (q, J = 7.0 Hz, 2 H), 4.88 (s, 2 H),7.06-7.14 (m, 2 H), 7.91-7.99 (m, 2 H), 10.16 (s, 1 H) DMSO-d6 276.18[M + H]+

Example 1 Methyl4-[4-(1-methyl-4-oxo-2,3-dihydroquinazolin-2-yl)-1H-pyrazol-5-yl]benzoate

2-(Methylamino)benzamide (500 mg) and acetic acid (50 μL) were added toan ethanol solution (20 mL) of methyl4-(4-formyl-1H-pyrazol-3-yl)benzoate (920 mg), and the mixture wasrefluxed under heating for 19 hours, and cooled to room temperature.Thereafter, the solvent was concentrated, and the residue was purifiedby silica gel chromatography (chloroform/methanol=99/1 to 95/5) to givethe title compound (1.34 g) as a white solid.

¹H-NMR (270 MHz, DMSO-d₆) δ: 3.87 (s, 3H), 5.84 (brs, 1H), 6.71 (d,J=8.2 Hz, 1H), 6.84 (t, J=7.4 Hz, 1H), 7.24-7.50 (m, 1H), 7.57 (brs,1H), 7.72-7.77 (m, 1H), 7.78-7.94 (m, 2H), 7.94-8.10 (m, 2H), 8.32 (s,1H), 8.53 (brs, 1H).

MS (ESI) m/z: 363.24 [M+H]⁺.

Example 24-[4-(1-Methyl-4-oxo-2,3-dihydroquinazolin-2-yl)-1H-pyrazol-5-yl]benzoicAcid

A 1 M potassium hydroxide solution (828 μL) was added to a methanolsolution (4 mL) of methyl4-[4-(1-methyl-4-oxo-2,3-dihydroquinazolin-2-yl)-1H-pyrazol-5-yl]benzoate(200 mg) at room temperature, and the mixture was stirred overnight,further heated to 60° C., stirred for 5 hours, and cooled to roomtemperature. Thereafter, 1 M hydrochloric acid (828 μL) was addeddropwise to perform neutralization. Water (4 mL) was added, the mixturewas stirred for 10 minutes, and the precipitated solid was then taken byfiltration, washed with water, and then dried by heating under reducedpressure to give the title compound (140 mg) as a white solid.

¹H-NMR (270 MHz, DMSO-d₆) δ: 5.81 (brs, 1H), 6.71 (brd, J=8.2 Hz, 1H),6.84 (t, J=7.4 Hz, 1H), 7.32-7.49 (m, 2H), 7.72-7.86 (m, 3H), 7.94-8.07(m, 2H), 8.54 (brs, 1H), 13.12 (brs, 2H).

MS (ESI) m/z: 349.22 [M+H]⁺.

Example 32-[3-(4-Aminophenyl)-1H-pyrazol-4-yl]-1-methyl-2,3-dihydroquinazolin-4-one

Ammonium chloride (61 mg) and iron powder (144 mg) were added to amixture of1-methyl-2-[3-(4-nitrophenyl)-1H-pyrazol-4-yl]-2,3-dihydroquinazolin-4-one(100 mg), ethanol (20 mL), water (7 mL) and tetrahydrofuran (5 mL), andthe resulting mixture was refluxed under heating for 3 hours, and cooledto room temperature. Thereafter, the insoluble matter was separated byfiltration through Celite, and washed with ethanol. The filtrate wasconcentrated, and the solid thus obtained was dissolved in a mixedsolvent (30 mL) of chloroform/methanol (9/1), washed with brine (10 mL),and then dried over magnesium sulfate. The solvent was concentrated, andthe residue thus obtained was purified by silica gel chromatography(chloroform/methanol=98/2 to 90/10) to give the title compound (73.7 mg)as a yellow solid.

¹H-NMR (270 MHz, DMSO-d₆) δ: 2.46 (s, 3H), 5.37 (brs, 2H), 5.60 (brs,1H), 6.57-6.73 (m, 3H), 6.83 (t, J=7.4 Hz, 1H), 7.12 (brs, 1H),7.19-7.32 (m, 2H), 7.39 (brt, J=7.1 Hz, 1H), 7.75 (brd, J=6.3 Hz, 1H),8.46 (brs, 1H), 12.82 (brs, 1H).

MS (ESI) m/z: 320.29 [M+H]⁺.

Example 4N-[4-[4-(1-Methyl-4-oxo-2,3-dihydroquinazolin-2-yl)-1H-pirazol-3-yl]phenyl]benzamide

2-[3-(4-Aminophenyl)-1H-pyrazol-4-yl]-1-methyl-2,3-dihydroquinazolin-4-one(20.0 mg) and benzoic acid (9.18 mg) were dissolved in DMF (0.5 mL),4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (20.8mg) was added, and the mixture was stirred overnight at roomtemperature. The solvent was concentrated, and the residue was purifiedby silica gel chromatography (chloroform/methanol=100/0 to 90/10) togive the title compound (21.6 mg) as a white solid.

¹H-NMR (270 MHz, DMSO-d₆) δ: 5.74 (brs, 1H), 6.71 (d, J=8.2 Hz, 1H),6.85 (t, J=7.3 Hz, 1H), 7.23-7.68 (m, 7H), 7.76 (dd, J=7.6, 1.6 Hz, 1H),7.84-8.02 (m, 4H), 8.44-8.59 (m, 1H), 10.38 (s, 1H).

MS (ESI) m/z: 424.41 [M+H]⁺.

Example 51-[3-[4-(1-Methyl-4-oxo-2,3-dihydroquinazolin-2-yl)-1H-pyrazol-3-yl]phenyl]-3-phenylurea

2-[3-(3-Aminophenyl)-1H-pyrazol-4-yl]-1-methyl-2,3-dihydroquinazolin-4-one(30 mg) was dissolved in tetrahydrofuran (1 mL), triethylamine (17.1 μL)was added, and the mixture was cooled with ice. To this solution wasadded phenyl isocyanate (11.2 μL), and the mixture was stirred at 0° C.for 3 hours. To the reaction mixture were added a mixed solvent (10 mL)of chloroform/methanol (9/1) and a 5% saline solution (10 mL), themixture was stirred, and the insoluble matter was separated byfiltration. The filtrate was concentrated, and the residue was purifiedby amino silica gel chromatography (chloroform/methanol=100/0 to 95/5)to give the title compound (12.5 mg) as a white solid.

¹H-NMR (270 MHz, CDCl₃) δ: 2.73 (s, 3H), 5.83 (d, J=3.3 Hz, 1H), 6.68(d, J=8.2 Hz, 1H), 6.72-6.81 (m, 1H), 6.85-7.03 (m, 3H), 7.11-7.26 (m,2H), 7.31-7.47 (m, 5H), 7.54-7.62 (m, 2H), 7.93 (dd, J=7.7, 1.5 Hz, 1H),8.09 (s, 1H), 9.11 (s, 1H).

MS (ESI) m/z: 439.45 [M+H]⁺.

Example 61-Methyl-2-[5-[4-[4-(4-methylpiperazin-1-yl)phenyl]phenyl]-1H-pirazol-4-yl]-2,3-dihydroquinazolin-4-one

2-[3-(4-Iodophenyl)-1H-pyrazol]-4-yl]-1-methyl-2,3-dihydroquinazolin-4-one(50.0 mg), 4-(4-methylpiperazin-1-yl)phenylboronic acid, pinacol ester(45.7 mg) and a [1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloride-dichloromethane adduct (4.8 mg) were suspended in a mixedsolvent of ethanol (1.6 mL) and toluene (0.4 mL), a 2 M sodium carbonateaqueous solution (87 μL) was added, and the mixture was heated to 125°C. and reacted for 3 hours in a microwave reaction apparatus. Thesolvent was concentrated, and the residue was purified by silica gelchromatography (chloroform/methanol=99/1 to 92/8) to give the titlecompound (42.1 mg) as a brown solid.

¹H-NMR (270 MHz, DMSO-d₆) δ: 2.25 (s, 3H), 3.16-3.25 (m, 4H), 5.60-5.90(m, 1H), 6.61-6.90 (m, 2H), 7.03 (brd, J=8.9 Hz, 2H), 7.15-7.33 (m, 1H),7.36-7.46 (m, 1H), 7.55-7.80 (m, 7H), 8.54 (brs, 1H), 13.20 (brs, 1H).

MS (ESI) m/z: 479.66 [M+H]⁺.

Example 71-Methyl-2-[4-[4-(4-morpholin-4-ylphenyl)phenyl]-2H-1,2,3-triazol-5-yl]-2,3-dihydroquinazolin-4-one

<Step 1>

2-[4-(4-Bromophenyl)-2H-1,2,3-triazol]-5-yl]-1-methyl-2,3-dihydroquinazolin-4-one(200 mg) was dissolved in tetrahydrofuran (4 mL), triethylamine (145 μL)was added, and the mixture was cooled with ice. To this solution wasadded trityl chloride (218 mg), and the mixture was then heated to roomtemperature, and stirred for 6 hours. Water (20 mL) was added, themixture was extracted with ethyl acetate (20 mL), and the organic layerswere washed with brine (20 mL). The aqueous layers were combined, andextracted with ethyl acetate (10 mL), and the organic layer was washedwith brine (10 mL). Subsequently, the organic layers were combined, anddried over magnesium sulfate. The solvent was concentrated, and theresidue was purified by silica gel column chromatography (hexane/ethylacetate=70/30 to 50/50) to give2-[4-(4-bromophenyl)-2-trityl-2H-1,2,3-triazol]-5-yl]-1-methyl-2,3-dihydroquinazolin-4-one(203 mg) as a white solid.

¹H-NMR (270 MHz, CDCl₃) δ: 2.63 (s, 3H), 6.02 (d, J=2.3 Hz, 1H), 6.36(d, J=2.0 Hz, 1H), 6.66 (d, J=8.2 Hz, 1H), 6.92 (t, J=7.5 Hz, 1H),7.03-7.12 (m, 5H), 7.22-7.33 (m, 10H), 7.33-7.40 (m, 1H), 7.41-7.48 (m,2H), 7.56-7.65 (m, 2H), 7.88 (dd, J=7.6, 1.6 Hz, 1H).

MS (ESI) m/z: 626.29, 628.42 [M+H]⁺.

<Step 2>

1-Methyl-2-[4-[4-(4-morpholin-4-ylphenyl)phenyl]-2-trityl-2H-1,2,3-triazol-5-yl]-2,3-dihydroquinazolin-4-one(61.9 mg) was prepared from2-[4-(4-bromophenyl)-2-trityl-2H-1,2,3-triazol]-5-yl]-1-methyl-2,3-dihydroquinazolin-4-one(100 mg) in a manner similar to that of Example 6.

MS(ESI) m/z: 709.86 [M+H]⁺

<Step 3>

1-Methyl-2-[4-[4-(4-morpholin-4-ylphenyl)phenyl]-2-trityl-2H-1,2,3-triazol-5-yl]-2,3-dihydroquinazolin-4-one(61.2 mg) was suspended in dichloromethane (1 mL), trifluoroacetic acid(0.5 mL) was added at room temperature, and the mixture was stirredovernight. The reaction mixture was diluted with ethyl acetate (20 mL),washed with saturated sodium bicarbonate water (20 mL) and brine (20mL), and dried over magnesium sulfate. The solvent was concentrated, andthe residue was purified by silica gel chromatography(chloroform/methanol=100/0 to 92/8) to give the title compound (17.1 mg)as a white solid.

¹H-NMR (270 MHz, DMSO-d₆) δ: 2.54-2.60 (m, 3H), 3.13-3.22 (m, 4H),3.71-3.81 (m, 4H), 6.06 (d, J=3.0 Hz, 1H), 6.70 (d, J=8.6 Hz, 1H), 6.81(t, J=7.4 Hz, 1H), 7.05 (d, J=8.9 Hz, 2H), 7.32-7.41 (m, 1H), 7.63 (d,J=8.9 Hz, 2H), 7.68-7.81 (m, 5H), 8.54 (d, J=3.0 Hz, 1H).

MS (ESI) m/z: 467.46 [M+H]⁺.

Example 8(2R)-2-[5-(4-Ethoxyphenyl)-2H-1,2,3-triazol-4-yl]-8-methyl-2,3-dihydro-1H-quinazolin-4-one

2-[5-(4-Ethoxyphenyl)-2H-1,2,3-triazol-4-yl]-8-methyl-2,3-dihydro-1H-quinazolin-4-one(136 mg) was optically resolved by high-performance liquidchromatography (methanol/TFA=100/0.05) with a chiral column(CHIRALPAC-IC; DAICEL) to give the title compound (59.4 mg; white solid)and an enantiomer thereof(2S)-2-[5-(4-ethoxyphenyl)-2H-1,2,3-triazol-4-yl]-8-methyl-2,3-dihydro-1H-quinazolin-4-one(60.1 mg; white solid)).

¹H-NMR (270 MHz, DMSO-d₆) δ: 1.33 (brt, J=6.9 Hz, 3H), 2.03 (brs, 3H),3.96-4.16 (m, 2H), 6.07 (brs, 1H), 6.32 (brs, 1H), 6.68 (brs, 1H), 7.01(brd, J=7.3 Hz, 2H), 7.15 (brd, J=6.9 Hz, 1H), 7.56 (brd, J=6.9 Hz, 1H),7.62-7.86 (m, 2H), 8.20 (brs, 1H), 14.84 (brs, 1H).

MS (ESI) m/z: 350.26 [M+H]⁺

[α]_(D) ²⁴=−148° (C=0.1; MeOH)

The compounds of Examples 9 to 81 shown in Tables 3 to 18 below wereprepared using the methods of Examples 1 to 8 and methods based thereon,and methods disclosed in literatures and methods based thereon.

TABLE 3 ¹H NMR ESI MS Example Compound Name Structural formula δ ppmSolvent m/z 9 2-(3-Phenyl-1H- pyrazol-4-yl)-2,3- dihydro-1H-quinazolin-4-one

5.49-6.02 (m, 1 H), 6.65-6.83 (m, 2 H), 6.92 (s, 1 H), 7.21- 7.31 (m, 1H), 7.34- 7.84 (m, 6 H), 7.93- 8.11 (m, 1 H), 8.16 (s, 1 H), 12.82-13.42(m, 1 H) DMSO-d6 291.22 [M + H]+ 10 1-Methyl-2-(3- phenyl-1H-pyrazol-4-yl)-2,3- dihydroquinazolin- 4-one

2.46 (s, 3 H), 5.55- 5.88 (m, 1 H), 6.69 (d, J = 8.2 Hz, 1 H), 6.84 (t,J = 7.4 Hz, 1 H), 7.21 (br s, 1 H), 7.32-7.54 (m, 4 H), 7.56-7.71 (m, 2H), 7.72-7.78 (m, 1 H), 8.52 (br s, 1 H). 12.78-13.41 (m, 1 H) DMSO-d6305.26 [M + H]+ 11 1-Methyl-2-[3-(4- phenylmethoxyphenyl)- 1H-pyrazol-4-yl]-2,3- dihydroquinazolin- 4-one

2.46 (s, 3 H), 5.16 (s, 2 H), 5.66 (br s, 1 H), 6.70 (d, J = 8.2 Hz, 1H), 6.85 (t, J = 7.6 Hz, 1 H), 7.12 (br d, J = 8.2 Hz, 2 H), 7.28-7.52(m, 7 H), 7.58 (br d, J = 8.2 Hz, 2 H), 7.75 (dd, J = 7.6, 1.6 Hz, 1 H),8.51 (br s, 1 H), 12.21- 13.46 (m, 1H) DMSO-d6 411.20 [M + H]+ 121-Ethyl-2-[3-(4- methoxyphenyl)- 1H-pyrazol-4-yl]- 2,3-dihydroquinazolin- 4-one

0.96 (t, J = 7.1 Hz, 3 H), 3.00-3.13 (m, 1 H), 3.27-3.41 (m, 1 H), 3.84(s, 3 H), 5.86- 5.89 (m, 1 H). 6.77 (d, J = 8.6 Hz, 1 H), 6.88 (t, J =7.4 Hz, 1 H), 6.96 (d, J = 8.2 Hz, 2 H), 7.37- 7.49 (m, 3 H), 7.54- 7.66(m, 1 H), 7.99 (dd, J = 7.6, 1.6 Hz, 1 H) CDCl3 349.32 [M + H]+ 13Methyl 4-[4-(1- ethyl-4-oxo-2,3- dihydroquinazolin- 2-yl)-1H-pyrazol-3-yl]benzoate

0.93 (br t, J = 6.3 Hz, 3 H), 2.90-3.10 (m, 1 H), 3.13-3.39 (m, 1 H),3.89 (s, 3 H), 5.90 (br s, 1 H), 6.73 (br d, J = 7.9 Hz, 1 H), 6.87 (brt, J = 7.3 Hz, 1 H), 7.33-7.64 (m, 5 H), 7.90-8.04 (m, 3 H) CDCl3 377.34[M + H]+

TABLE 4 ESI Exam- MS ple Compound Name Structural formula ¹H NMR δ ppmSolvent m/z 14 1- (Cyclopropyl- methyl)-2-[5-(4- methoxyphenyl)-1H-pyrazol-4-yl]- 2,3- dihydro- quinazolin- 4-one

−0.26-−0.06 (m, 2 H), 0.11-0.29 (m, 2 H), 0.62-0.83 (m, 1 H), 3.67-4.06(m, 5 H), 5.85 (br s, 1 H), 6.77- 6.89 (m, 2 H), 6.99- 7.09 (m, 2 H),7.30- 7.46 (m, 2 H), 7.51- 7.61 (m, 2 H), 7.76 (br d, J = 7.3 Hz, 1 H),8.58 (br s, 1 H) DMSO-d6 375.28 [M + H]+ 15 2-[5-(3- Methoxyphenyl)-1H-pyrazol-4-yl]- 1-methyl-2,3- dihydro- quinazolin- 4-one

2.54 (s, 3 H), 3.68 (s, 3 H), 5.73 (d, J = 2.0 Hz, 1 H), 6.61 (d, J =8.2 Hz, 1 H), 6.80-6.89 (m, 2 H), 6.96-7.08 (m, 2 H), 7.15-7.25 (m, 1H), 7.29-7.42 (m, 2 H), 7.86-7.99 (m, 2 H) CDCl3 335.26 [M + H]+ 161-Methyl-2-[3-(4- nitrophenyl)-1H- pyrazol-4-yl]-2,3- dihydro-quinazolin- 4-one

2.55 (s, 3 H), 5.86 (d, J = 2.6 Hz, 1 H), 6.76 (d, J = 8.2 Hz, 1 H),6.81- 6.90 (m, 1 H), 7.38- 7.46 (m, 1 H), 7.57 (br s, 1 H), 7.74 (dd, J= 7.6, 1.6 Hz, 1 H), 8.00 (d, J = 8.9 Hz, 2 H), 8.28 (d, J = 8.9 Hz, 2H), 8.52 (d, J = 2.3 Hz, 1 H) DMSO-d6 350.25 [M + H]+ 171-Methyl-2-[3-(4- phenylphenyl)- 1H-pyrazol-4-yl]- 2,3- dihydro-quinazolin- 4-one

5.78 (br s, 1 H), 6.70- 6.78 (m, 1 H), 6.79- 6.93 (m, 1 H), 7.34- 7.61(m, 5 H), 7.67- 7.88 (m, 7 H), 8.54 (br s, 1 H), 13.16 (br s, 1 H)DMSO-d6 381.39 [M + H]+ 18 1-Methyl-2-[3-(4- phenoxyphenyl)-1H-pyrazol-4-yl]- 2,3- dihydro- quinazolin- 4-one

5.48-5.90 (m, 1 H), 6.71 (d, J = 8.2 Hz, 1 H), 6.84 (t, J = 7.4 Hz, 1H), 6.94-7.30 (m, 6 H), 7.34-7.49 (m, 3 H), 7.64 (br s, 2 H), 7.74 (brd, J = 7.6 Hz, 1 H), 8.48 (br s, 1 H), 12.68- 13.91 (m, 1 H) DMSO-d6397.89 [M + H]+

TABLE 5 ESI Exam- MS ple Compound Name Structural formula ¹H NMR δ ppmSolvent m/z 19 2-[3-(4- Iodophenyl)-1H- pyrazol-4-yl]-1- methyl-2,3-dihydro- quinazolin- 4-one

5.58-5.84 (m, 1 H), 6.67-6.77 (m, 1 H), 6.85 (t, J = 7.4 Hz, 1 H),7.32-7.62 (m, 4 H), 7.75 (br t, J = 7.6 Hz, 2 H), 7.87 (br d, J = 8.6Hz, 1 H), 8.40- 8.58 (m, 1 H), 12.78- 13.39 (m, 1 H) DMSO-d6 431.31 [M +H]+ 20 2-[3-(3- Bromophenyl)- 1H-pyrazol-4-yl]- 1-methyl-2,3- dihydro-quinazolin- 4-one

5.59-5.83 (m, 1 H), 6.65-6.78 (m, 1 H), 6.85 (t, J = 7.4 Hz, 1 H),7.31-7.97 (m, 7 H), 8.40-8.60 (m, 1 H), 12.97-13.36 (m, 1 H) DMSO-d6383.24, 385.22 [M + H]+ 21 2-[3-(4- Fluorophenyl)- 1H-pyrazol-4-yl]-1-methyl-2,3- dihydro- quinazolin- 4-one

2.48 (br s, 3 H), 5.54- 5.86 (m, 1 H), 6.71 (br d, J = 8.2 Hz, 1 H),6.84 (td, J = 7.4, 1.0 Hz, 1 H), 7.15-7.81 (m, 7 H), 8.40-8.59 (m, 1 H),12.71-13.37 (m, 1 H) DMSO-d6 323.27 [M + H]+ 22 1-Methyl-2-[3-(3-phenylphenyl)- 1H-pyrazol-4-yl]- 2,3- dihydro- quinazolin- 4-one

5.65-5.93 (m, 1 H), 6.74 (br s, 1 H), 6.86 (t, J = 7.4 Hz, 1 H), 7.21-7.51 (m, 5 H), 7.56- 7.81 (m, 6 H), 7.87- 8.16 (m, 1 H), 8.40- 8.68 (m,1 H), 12.85- 13.46 (m, 1 H) DMSO-d6 381.31 [M + H]+ 23 1-Methyl-2-[5-[3-[4-(4- methylpiperazin- 1- yl)phenyl]phenyl]- 1H-pyrazol-4-yl]- 2,3-dihydro- quinazolin- 4-one

2.17-2.27 (m, 3 H), 2.48-2.53 (m, 7 H), 3.12-3.23 (m, 4 H), 5.62-5.94(m, 1 H), 6.60-7.06 (m, 4 H), 7.20-8.04 (m, 9 H), 8.40-8.63 (m, 1 H),12.85-13.36 (m, 1 H) DMSO-d6 479.50 [M + H]+ 24 2-[3-[4-(3- Hydroxyphe-nyl)phenyl]-1H- pyrazol- 4-yl]-1-methyl- 2,3- dihydro- quinazolin- 4-one

5.76 (br s, 1 H), 6.68- 6.92 (m, 3 H), 7.04- 7.19 (m, 2 H), 7.22- 7.34(m, 1 H), 7.41 (br t, J = 7.1 Hz, 1 H), 7.49- 7.91 (m, 6 H), 8.56 (br s,1 H), 9.57 (br s, 1 H), 12.78-13.48 (m, 1 H) DMSO-d6 397.38 [M + H]+

TABLE 6 ESI MS Example Compound Name Structural formula ¹H NMR δ ppmSolvent m/z 25 1-Methyl-2-[5-[4- [4-[(4- methylpiperazin- 1-yl)methyl]phe- nyl]phenyl]-1H- pyrazol-4-yl]-2,3- dihydro- quinazolin-4-one

2.15 (s, 3 H), 2.23- 2.47 (m, 8 H), 3.49 (s, 2 H), 5.62-5.90 (m, 1 H),6.73 (br d, J = 8.2 Hz, 1 H), 6.85 (t, J = 7.6 Hz, 1 H), 7.17- 7.48 (m,4 H), 7.64-7.87 (m, 7 H), 8.55 (br s, 1 H), 12.82-13.40 (m, 1 H) DMSO-d6493.57 [M + H]+ 26 1-Methyl-2-[5-[4- [3-[(4- methylpiperazin- 1-yl)methyl]phe- nyl]phenyl]-1H- pyrazol-4-yl]-2,3- dihydro- quinazolin-4-one

2.14 (s, 3 H), 2.20- 2.49 (m, 8 H), 3.53 (s, 2 H), 5.78 (br s, 1 H),6.73 (br d, J = 7.9 Hz, 1 H), 6.85 (br t, J = 7.4 Hz, 1 H), 7.17-7.53(m, 4 H), 7.55-7.89 (m, 7 H), 8.56 (br s, 1 H), 12.73-13.46 (m, 1 H)DMSO-d6 493.57 [M + H]+ 27 1-Methyl-2-[3-(4- (2,2,2- trifluorometh-oxy)phenyl]-1H- pyrazol-4-yl]-2,3- dihydro- quinazolin- 4-one

2.64 (s, 3 H), 4.31 (q, J = 7.7 Hz, 2 H), 5.75 (s, 1 H), 6.70 (br d, J =8.1 Hz, 1 H), 6.84-6.98 (m, 3 H), 7.36 (br d, J = 8.6 Hz, 2 H), 7.40-7.55 (m, 3 H), 7.95 (dd, J = 7.7, 1.3 Hz, 1 H) CDCl3 403.34 [M + H]+ 282-[3-(3- Fluorophenyl)- 1H-pyrazol-4-yl]- 1-methyl-2,3- dihydro-quinazolin- 4-one

5.75 (br s, 1 H), 6.70 (br d, J = 8.1 Hz, 1 H), 6.83 (br t, J = 7.3 Hz,1 H), 7.05-7.61 (m, 6 H), 7.72 (br d, J = 7.6 Hz, 1 H), 8.48 (br s, 1H), 12.63-13.46 (m, 1 H) DMSO-d6 323.28 [M + H]+ 29 1-Methyl-2-[3-[4-(4-morpholin-4- yl)phenyl)ph- enyl]-1H- pyrazol-4-yl]- 2,3- dihydro-quinazolin- 4-one

3.15-3.19 (m, 4 H), 3.51-3.77 (m, 4 H), 5.74 (br s, 1 H), 6.73 (d, J =8.1 Hz, 1 H), 6.85 (t, J = 8.1 Hz, 1 H), 7.04 (d, J = 10.8 Hz, 2 H),7.24 (br s, 1 H), 7.37- 7.44 (m, 1 H), 7.61- 7.78 (m, 7 H), 8.54 (br s,1 H), 12.96-13.20 (m, 1 H) DMSO-d6 466.40 [M + H]+

TABLE 7 ESI Exam- MS ple Compound Name Structural formula ¹H NMR δ ppmSolvent m/z 30 1-Methyl-2-[3-[3- (4-morpholin-4- yl)phenyl)phenyl]-1H-pyrazol-4-yl]- 2,3- dihydroquinazolin- 4-one

3.15 (s, 4 H), 3.74- 3.77 (m, 4 H), 5.78 (s, 1 H), 6.73 (d, J = 8.1 Hz,1 H), 6.85 (t, J = 8.1 Hz, 1 H), 6.99 (d, J = 8.1 Hz, 2 H), 7.38-7.65(m, 7 H), 7.75-7.78 (m, 1 H), 7.92 (br s, 1 H), 8.42 (s, 1 H) DMSO-d6466.37 [M + H]+ 31 4-[4-(1-Methyl-4- oxo-2,3- dihydroquinazolin-2-yl)-1H-pyrazol- 3-yl]benzonitrile

5.81 (d, J = 2.7 Hz, 1 H), 6.75 (d, J = 8.1 Hz, 1 H), 6.86 (t, J = 8.1Hz, 1 H), 7.38-7.45 (m, 1 H), 7.54 (br s, 1 H), 7.74 (dd, J = 8.1, 2.7Hz, 1 H), 7.90 (s, 4 H), 8.51 (d, J = 2.7 Hz, 1 H), 13.3 (br s, 1 H)DMSO-d6 330.28 [M + H]+ 32 1-Methyl-2-[5-[3- [4-[(4- methylpiperazin- 1-yl)methylphe- nyl]phenyl]-1H- pyrazol-4-yl]-2,3- dihydroquinazolin-4-one

2.16 (s, 3 H), 2.36 (br s, 8 H), 3.47 (s, 2 H), 5.76 (br s, 1 H), 6.73(d, J = 8.1 Hz, 1 H), 6.85 (t, J = 8.1 Hz, 1 H), 7.25- 7.44 (m, 3 H),7.50- 7.78 (m, 7 H), 7.94- 8.07 (m, 1 H), 8.54 (br s, 1 H), 13.04-13.28(m, 1 H) DMSO-d6 493.58 [M + H]+ 33 1-Methyl-2-[5-[3- [3-[(4-methylpiperazin- 1- yl)methylphe- nyl]phenyl]-1H- pyrazol-4-yl]-2,3-dihydroquinazolin- 4-one

2.15 (s, 3 H), 2.35 (br s, 8 H), 3.51 (s, 2 H), 5.79 (br s, 1 H), 6.73-6.76 (m, 1 1H), 6.86 (t, J = 8.1 Hz, 1 H), 7.25- 7.78 (m, 10 H), 7.95-8.12 (m, 1 H), 8.53 (br s, 1 H), 13.06-13.31 (m, 1 H) DMSO-d6 493.56[M + H]+ 34 2-[5-[4-[4- (Dimethyl- amino)phenyl]phe- nyl]-1H-pyrazol-4-yl]-1- methyl-2,3- dihydroquinazolin- 4-one

2.95 (s, 6 H), 5.73 (br s, 1 H), 6.69-6.90 (m, 4 H), 7.41 (br t, J = 7.1Hz, 2 H), 7.53-7.83 (m, 7 H), 8.55 (br s, 1 H), 12.72-13.37 (m, 1 H)DMSO-d6 424.39 [M + H]+

TABLE 8 Exam- Compound ¹H NMR ESI MS ple Name Structural formula δ ppmSolvent m/z 35 2-[5-[3-[4- (Dimethyl- amino)phe- nyl]phenyl]- 1H-pyrazol-4-yl]- 1-methyl-2,3- dihydro- quinazolin- 4-one

2.93 (s, 6 H), 5.76 (br s, 1 H), 6.66-6.91 (m, 4 H), 7.31-8.01 (m, 9 H),8.54 (br s, 1 H), 12.69-13.56 (m, 1 H) DMSO- d6 424.38 [M + H]+ 36 Ethyl2- [4-[4-[4-(1- methyl- 4-oxo- 2,3-dihydro- quinazolin- 2-yl)-1H-pyrazol- 5-yl]phe- nyl]phe- nyl]acetate

1.20 (t, J = 7.1 Hz, 3 H), 3.72 (s, 2 H), 4.10 (q, J = 6.9 Hz, 2 H),5.65- 5.89 (m, 1 H), 6.73 (br d, J = 7.9 Hz, 1 H), 6.85 (t, J = 7.4 Hz,1 H), 7.32-7.47 (m, 3 H), 7.57 (br s, 1 H), 7.65-7.84 (m, 7 H), 8.55 (brd, J = 14.2 Hz, 1 H), 12.87-13.38 (m, 1 H) DMSO- d6 467.41 [M + H]+ 37Ethyl 2- [4-[3-[4-(1- methyl- 4-oxo- 2,3-dihydro- quinazolin- 2-yl)-1H-pyrazol-5- yl]phe- nyl]phe- nyl]acetate

1.20 (t, J = 7.3 Hz, 3 H), 3.70 (br d, J = 6.3 Hz, 2 H), 4.10 (q, J =7.3 Hz, 2 H), 5.65-5.94 (m, 1 H), 6.73 (br s, 1 H), 6.86 (t, J = 7.3 Hz,1 H), 7.25-7.80 (m, 10 H), 7.86-8.15 (m, 1 H), 8.38-8.66 (m, 1 H),12.86-13.41 (m, 1 H) DMSO- d6 467.40 [M + H]+ 38 1-Methyl-2-[5-[4-[3-(4- methyl- piperazin-1- yl)phe- nyl]phenyl]- 1H-pyrazol-4-yl]-2,3- dihydro- quinazolin- 4-one

2.23 (s, 3 H), 3.15- 3.27 (m, 4 H), 5.60- 5.94 (m, 1 H), 6.73 (br d, J =7.9 Hz, 1 H), 6.86 (t, J = 7.6 Hz, 1 H), 6.96 (br d, J = 6.9 Hz, 1 H),7.06-7.47 (m, 5 H), 7.62-7.85 (m, 5 H), 8.55 (br d, J = 11.5 Hz, 1 H),12.87-13.36 (m, 1 H) DMSO- d6 479.47 [M + H]+

TABLE 9 ESI MS Example Compound Name Structural formula ¹H NMR δ ppmSolvent m/z 39 1-Methyl-2-[3-[4- (1H-pyrrolo[2,3- b]pyridin-4-yl)phenyl]-1H- pyrazol-4-yl]-2,3- dihydroquinazolin- 4-one

2.56 (s, 3 H), 5.63- 5.99 (m,1 H), 6.63- 6.90 (m, 3 H), 7.08- 8.02 (m,10 H), 8.58 (br d, J = 11.2 Hz, 1 H), 11.84 (br s, 1 H), 12.89- 13.41(m, 1 H) DMSO-d6 421.33 [M + H]+ 40 1-Methyl-2-[3-(4- quinolin-4-ylphenyl)-1H- pyrazol-4-yl]-2,3- dihydroquinazolin- 4-one

2.58 (s, 3 H), 5.72- 5.96 (m, 1 H), 6.70- 6.90 (m, 2 H), 7.35- 8.00 (m,11 H), 8.14 (br d, J = 8.2 Hz, 1 H), 8.60 (br d, J = 11.9 Hz, 1 H), 8.98(br s, 1 H), 12.89- 13.48 (m, 1 H) DMSO-d6 432.33 [M + H]+ 411-Methyl-2-[3-[4- (4-piperazin-1- yl)phenyl]phenyl]- 1H-pyrazol-4-yl]-2,3- dihydroquinazolin- 4-one

2.78-2.92 (m, 4 H), 3.03-3.17 (m, 4 H), 5.76 (br s, 1 H), 6.72 (br d, J= 7.9 Hz, 1 H), 6.85 (br t, J = 7.1 Hz, 1 H), 7.01 (br d, J = 7.9 Hz, 2H), 7.23-7.87 (m, 9 H), 8.54 (br s, 1 H) DMSO-d6 465.46 [M + H]+ 422-[3-(3- Chlorophenyl)- 1H-pyrazol-4-yl]- 1-methyl-2,3-dihydroquinazolin- 4-one

2.63 (s, 3 H), 5.75 (d, J = 2.3 Hz, 1 H), 6.68 (d, J = 8.2 Hz, 1 H),6.91 (t, J = 7.5 Hz, 1 H), 7.33- 7.54 (m, 6 H), 7.99 (dd, J = 7.6, 1.6Hz, 1 H) CDCl3 339.29 [M + H]+ 43 2-[3-(4-Bromo-3- fluorophenyl)-1H-pyrazol-4-yl]-1- methyl-2,3- dihydroquinazolin- 4-one

2.53 (s, 3 H), 5.80 (br s, 1 H), 6.75 (d, J = 8.2 Hz, 1 H), 6.85 (t, J =7.4 Hz, 1 H), 7.33-7.62 (m, 3 H), 7.64-7.82 (m, 3 H), 8.50 (br s, 1 H),13.18 (br s, 1 H) DMSO-d6 401.18, 403.17 [M + H]+

TABLE 10 ESI MS Example Compound Name Structural formula ¹H NMR δ ppmSolvent m/z 44 2-[5-[3-Fluoro-4- [4-(4- methylpiperazin- 1-yl)phenyl]phenyl]- 1H-pyrazol-4-yl]- 1-methyl-2,3- dihydroquinazolin-4-one

2.23 (s, 3 H), 2.39- 2.47 (m, 4 H), 2.54 (s, 3 H), 3.10-3.27 (m, 4 H),5.66-5.91 (m, 1 H), 6.76 (br d, J = 3.6 Hz, 1 H), 6.86 (t, J = 7.4 Hz, 1H), 7.04 (br d, J = 8.6 Hz, 2 H), 7.35-7.68 (m, 7 H), 7.75 (dd, J = 7.6,1.6 Hz, 1 H), 8.52 (br s, 1 H), 12.78- 13.47 (m, 1 H) DMSO-d6 497.54[M + H]+ 45 2-[3-(3-Fluoro-4- phenylmethoxy- phenyl)-1H-pyrazol-4-yl]-1-methyl- 2,3- dihydroquinazolin- 4-one

5.23 (s, 2 H), 5.71 (br s, 1 H), 6.72 (d, J = 8.2 Hz, 1 H), 6.85 (t, J =6.9 Hz, 1 H), 7.30- 7.59 (m, 10 H), 7.74 (dd, J = 7.6, 1.6 Hz, 1 H),8.48 (br s, 1 H) DMSO-d6 429.26 [M + H]+ 46 2-[5-(4- Ethoxyphenyl)-1H-pyrazol-4-yl]- 1-methyl-2,3- dihydroquinazolin- 4-one

1.34 (t, J = 6.9 Hz, 3 H), 2.46 (s, 3 H), 4.07 (q, J = 6.9 Hz, 2 H),5.61- 5.70 (m, 1 H), 6.70 (d, J = 8.2 Hz, 1 H), 6.84 (t, J = 7.3 Hz, 1H), 7.01 (d, J = 8.9 Hz, 2 H), 7.24- 7.47 (m, 2 H), 7.54 (d, J = 8.6 Hz,2 H), 7.75 (dd, J = 7.7, 1.5 Hz, 1 H), 8.47 (d, J = 2.6 Hz, 1 H), 12.98(br s, 1 H) DMSO-d6 349.46 [M + H]+ 47 2-[3-(3,5- Difluorophenyl)-1H-pyrazol-4-yl]- 1-methyl-2,3- dihydroquinazolin- 4-one

2.53 (s, 3 H), 5.81 (br s, 1 H), 6.75 (d, J = 8.2 Hz, 1 H), 6.86 (t, J =7.4 Hz, 1 H), 7.10-7.67 (m, 5 H), 7.74 (d, J = 6.3 Hz, 1 H), 8.48 (br s,1 H), 12.62-13.75 (m, 1 H) DMSO-d6 341.33 [M + H]+

TABLE 11 ESI Exam- MS ple Compound Name Structural formula ¹H NMR δ ppmSolvent m/z 48 1-Methyl-2-[3-(4- (trifluorometh- oxy)phenyl)-1H-pyrazol-4-yl]-2,3- dihydroquinazolin- 4-one

5.75 (br s, 1 H), 6.73 (br d, J = 8.2 Hz, 1 H), 6.85 (t, J = 7.3 Hz, 1H), 7.25-7.60 (m, 4 H), 7.65-7.88 (m, 3 H), 8.51 (br s, 1 H), 13.08 (brs, 1 H) DMSO-d6 389.35 [M + H]+ 49 2-[5-(3,5-Difluoro- 4-methoxyphenyl)- 1H-pyrazol-4-yl]- 1-methyl-2,3- dihydroquinazolin- 4-one

2.53 (s, 3 H), 3.96 (s, 3 H), 5.78 (br s, 1 H), 6.75 (d, J = 8.2 Hz, 1H), 6.85 (t, J = 7.4 Hz, 1 H), 7.34-7.62 (m, 4 H), 7.73 (dd, J = 7.6,1.6 Hz, 1 H), 8.48 (br s, 1 H), 13.12 (br s, 1 H) DMSO-d6 371.30 [M +H]+ 50 2-[5-(4- Methoxyphenyl)- 1H-pyrazol-4-yl]- 8-methyl-2,3-dihydro-1H- quinazolin-4-one

2.07 (s, 3 H), 3.78 (s, 3 H), 5.74 (br s, 1 H), 6.04 (br s, 1 H), 6.69(t, J = 7.4 Hz, 1 H), 7.03 (br d, J = 6.3 Hz, 2 H), 7.16 (d, J = 6.6 Hz,1 H), 7.56 (m, J = 7.6 Hz, 4 H), 8.15 (s, 1 H), 12.76- 13.26 (m, 1 H)DMSO-d6 335.27 [M + H]+ 51 8-Methyl-2-[5-[4- [4-(4- methylpiperazin- 1-yl)phenyl]phenyl]- 1H-pyrazol-4-yl]- 2,3-dihydro-1H- quinazolin-4-one

2.08 (s, 3 H), 2.22 (s, 3 H), 2.41-2.48 (m, 4 H), 3.14-3.24 (m, 4 H),5.85 (br s, 1 H), 6.09 (br s, 1 H), 6.70 (t, J = 7.6 Hz, 1 H), 7.02 (brd, J = 8.9 Hz, 2 H), 7.17 (d, J = 6.6 Hz, 1 H), 7.53-7.80 (m, 8 H), 8.22(s, 1 H), 12.96-13.28 (m, 1 H) DMSO-d6 479.50 [M + H]+

TABLE 12 ESI Exam- MS ple Compound Name Structural formula ¹H NMR δ ppmSolvent m/z 52 11-[5-(4- Methoxyphenyl)- 1H-pyrazol-4-yl]-1,10-diazatri- cyclo[6.3.1.0^(4,12)]do- deca- 4(12),5,7-trien-9- one

2.64-2.82 (m, 1 H), 2.83-3.01 (m, 2 H), 3.03-3.24 (m, 1 H), 3.77 (s, 3H), 5.40 (br s, 1 H), 6.79 (br t, J = 7.4 Hz, 1 H), 7.01 (br s, 2 H),7.25 (br d, J = 6.9 Hz, 1 H), 7.36 (br d, J = 7.6 Hz, 1 H), 7.45-7.85(m, 3 H), 8.15 (s, 1 H), 12.86- 13.27 (m, 1 H) DMSO-d6 347.35 [M + H]+53 2-[5-(4- Methoxyphenyl)- 1H-pyrazol-4-yl]- 1,7-dimethyl-2,3-dihydroquinazolin- 4-one

2.28 (s, 3 H), 2.45 (s, 3 H), 3.80 (s, 3 H), 5.52-5.77 (m, 1 H), 6.52(s, 1 H), 6.66 (d, J = 7.6 Hz, 1 H), 6.90- 7.10 (m, 2 H), 7.12- 7.31 (m,1 H), 7.43- 7.67 (m, 3 H), 8.40 (br s, 1 H), 12.64- 13.17 (m, 1 H)DMSO-d6 349.24 [M + H]+ 54 8-Methyl-2-[3-(4- (2,2,2-trifluoro-ethoxy)phenyl)- 1H-pyrazol- 4-yl]-2,3-dihydro- 1H-quinazolin-4- one

2.08 (s, 3 H), 4.79 (q, J = 8.9 Hz, 2 H), 5.75 (br s, 1 H), 6.06 (br s,1 H), 6.69 (t, J = 7.6 Hz, 1 H), 7.03-7.25 (m, 3 H), 7.50-8.03 (m, 4 H),8.17 (s, 1 H), 12.79-13.28 (m, 1 H) DMSO-d6 403.25 [M + H]+ 55 2-[5-(4-Ethoxyphenyl)- 1H-pyrazol-4-yl]- 8-methyl-2,3- dihydro-1H-quinazolin-4-one

1.33 (t, J = 6.9 Hz, 3 H), 2.07 (s, 3 H), 4.05 (q, J = 6.9 Hz, 2 H),5.75 (s, 1 H), 6.02 (s, 1 H), 6.69 (t, J = 7.6 Hz, 1 H), 7.01 (br d, J =8.6 Hz, 2 H), 7.16 (d, J = 6.6 Hz, 1 H), 7.51-7.62 (m, 3 H), 7.77 (br s,1 H), 8.13 (s, 1 H), 12.99 (br s, 1 H) DMSO-d6 349.40 [M + H]+

TABLE 13 ESI Exam- MS ple Compound Name Structural formula ¹H NMR δ ppmSolvent m/z 56 2-[5-(3-Fluoro-4- methoxyphenyl)- 1H-pyrazol-4-yl]-8-methyl-2,3- dihydro-1H- quinazolin-4-one

2.08 (s, 3 H), 3.86 (s, 3 H), 5.78 (s, 1 H), 6.06 (s, 1 H), 6.70 (t, J =7.4 Hz, 1 H), 7.14-7.30 (m, 2 H), 7.45-7.60 (m, 3 H), 7.83 (br s, 1 H),8.15 (s, 1 H), 13.07 (br s, 1 H) DMSO-d6 353.40 [M + H]+ 578-Ethyl-2-[3-(4- methoxyphenyl)- 1H-pyrazol-4-yl]- 2,3-dihydro-1H-quinazolin-4-one

1.05 (t, J = 7.4 Hz, 3 H), 2.38-2.47 (m, 2 H), 3.77 (s, 3 H), 5.67- 5.80(m, 1 H), 6.04- 6.17 (m, 1 H), 6.73 (t, J = 7.6 Hz, 1 H), 6.94- 7.10 (m,2 H), 7.17 (dd, J = 7.4, 1.5 Hz, 1 H), 7.49-7.98 (m, 4 H), 8.17 (s, 1H), 12.80- 13.17 (m, 1 H) DMSO-d6 349.36 [M + H]+ 58 2-[5-(4-Methoxyphenyl)- 2H-1,2,3-triazol- 4-yl]-1-methyl- 2,3- dihydro-quinazolin- 4-one

3.80 (s, 3 H), 5.98 (d, J = 3.0 Hz, 1 H), 6.68 (d, J = 8.2 Hz, 1 H),6.81 (t, J = 7.6 Hz, 1 H), 7.04 (d, J = 8.6 Hz, 2 H), 7.31- 7.40 (m, 1H), 7.61- 7.75 (m, 3 H), 8.50 (d, J = 3.0 Hz, 1 H) DMSO-d6 336.33 [M +H]+ 59 2-[5-(4- Methoxyphenyl)- 2H-1,2,3-triazol- 4-yl]-2,3-dihydro-1H-quinazolin-4- one

3.78 (s, 3 H), 6.10 (s, 1 H), 6.67-6.81 (m, 2 H), 6.96-7.14 (m, 3 H),7.27 (br t, J = 7.3 Hz, 1 H), 7.62- 7.89 (m, 3 H), 8.24 (br s, 1 H)DMSO-d6 322.24 [M + H]+ 60 2-[4-(4- Bromophenyl)- 2H-1,2,3-triazol-5-yl]-1-methyl- 2,3- dihydro- quinazolin- 4-one

2.56 (s, 3 H), 6.04 (br s, 1 H), 6.69 (br d, J = 7.9 Hz, 1 H), 6.81 (brt, J = 7.1 Hz, 1 H), 7.28-7.56 (m, 2 H), 7.61-7.76 (m, 5 H), 8.53 (br s,1 H) DMSO-d6 384.19, 386.17 [M + H]+

TABLE 14 ESI MS Example Compound Name Structural formula ¹H NMR δ ppmSolvent m/z 61 1-Methyl-2-[5-[3- [4-(4- methylpiperazin- 1-yl)phenyl]phenyl]- 2H-1,2,3-triazol- 4-yl]-2,3- dihydro- quinazolin-4-one

2.26 (s, 3 H), 2.56 (s, 3 H), 3.15-3.22 (m, 4 H), 6.08 (d, J = 2.6 Hz, 1H), 6.71 (d, J = 7.9 Hz, 1 H), 6.82 (t, J = 7.3 Hz, 1 H), 6.95 (d, J =8.9 Hz, 2 H), 7.35-7.75 (m, 7 H), 7.99 (s, 1 H), 8.54 (d, J = 2.6 Hz, 1H) DMSO-d6 480.49 [M + H]+ 62 1-Methyl-2-[4-[3- (4-morpholin-4-ylphenyl)phenyl]- 2H-1,2,3-triazol- 5-yl]-2,3- dihydro- quinazolin-4-one

2.55 (s, 3 H), 3.06- 3.20 (m, 4 H), 3.66- 3.86 (m, 4 H), 6.11 (br s, 1H), 6.71 (br d, J = 7.9 Hz, 1 H), 6.83 (br t, J = 7.3 Hz, 1 H), 6.97 (brs, 2 H), 7.38 (br t, J = 6.9 Hz, 1 H), 7.47-7.79 (m, 6 H), 8.03 (br s, 1H), 8.55 (br s, 1 H), 14.99 (br s, 1 H) DMSO-d6 467.46 [M + H]+ 632-[5-(4- Ethoxyphenyl)- 2H-1,2,3-triazol- 4-yl]-1-methyl- 2,3- dihydro-quinazolin- 4-one

1.35 (t, J = 6.9 Hz, 3 H), 4.07 (q, J = 6.9 Hz, 2 H), 5.97 (d, J = 3.0Hz, 1 H), 6.67 (d, J = 7.9 Hz, 1 H), 6.81 (t, J = 7.4 Hz, 1 H), 7.01 (d,J = 8.9 Hz, 2 H), 7.32-7.40 (m, 1 H), 7.63 (d, J = 8.9 Hz, 2 H), 7.71(dd, J = 7.6, 1.6 Hz, 1 H), 8.48 (d, J = 3.3 Hz, 1 H) DMSO-d6 350.34[M + H]+ 64 1-Methyl-2-[4-[4- (2,2,2-trifluoro- ethoxy)phenyl]-2H-1,2,3- triazol-5-yl]-2,3- dihydro- quinazolin- 4-one

2.53 (s, 3 H), 4.83 (q, J = 8.9 Hz, 2 H), 5.99 (d, J = 2.6 Hz, 1 H),6.68 (d, J = 8.2 Hz, 1 H), 6.81 (t, J = 7.4 Hz, 1 H), 7.16 (d, J = 8.6Hz, 2 H), 7.30- 7.43 (m, 1 H), 7.63- 7.78 (m, 3 H), 8.51 (d, J = 3.0 Hz,1 H) DMSO-d6 404.28 [M + H]+

TABLE 15 ESI Exam- MS ple Compound Name Structural formula ¹H NMR δ ppmSolvent m/z 65 2-[5-(4- Methoxyphenyl)- 2H-1,2,3-triazol-4-yl]-8-methyl- 2,3-dihydro-1H- quinazolin-4-one

2.04 (s, 3 H), 3.79 (s, 3 H), 6.07 (s, 1 H), 6.35 (br s, 1 H), 6.69 (t,J = 7.4 Hz, 1 H), 7.03 (d, J = 8.9 Hz, 2 H), 7.15 (d, J = 7.3 Hz, 1 H),7.56 (d, J = 6.9 Hz, 1 H), 7.74 (br d, J = 8.6 Hz, 2 H), 8.23 (br s, 1H) DMSO-d6 336.23 [M + H]+ 66 2-[4-(4- Bromophenyl)- 2H-1,2,3-triazol-5-yl]-8-methyl- 2,3-dihydro-1H- quinazolin-4-one

2.03 (s, 3 H), 6.11 (s, 1 H), 6.39 (br s, 1 H), 6.69 (t, J = 7.4 Hz, 1H), 7.15 (br d, J = 6.9 Hz, 1 H), 7.52-7.84 (m, 3 H), 8.26 (br s, 1 H)DMSO-d6 384.27, 386.26 [M + H]+ 67 8-Hydroxy-2-[5- (4- methoxyphenyl)-2H-1,2,3-triazol- 4-yl]-2,3-dihydro- 1H-quinazolin-4- one

3.79 (s, 3 H), 6.00 (br s, 1 H), 6.08 (s, 1 H), 6.59 (t, J = 7.9 Hz, 1H), 6.81 (dd, J = 7.7, 1.2 Hz, 1 H), 7.03 (d, J = 8.6 Hz, 2 H), 7.18 (d,J = 7.6 Hz, 1 H), 7.75 (br d, J = 8.9 Hz, 2 H), 8.19 (br s, 1 H), 9.54(br s, 1 H) DMSO-d6 338.37 [M + H]+ 68 2-[5-(4- Methoxyphenyl)-2H-1,2,3-triazol- 4-yl]-10-oxa-1,3- diazatri- cyclo[7.3.1.0^(5,13)]tri-deca-5,7,9(13)-trien-4- one

2.63-2.76 (m, 1 H), 2.88-2.99 (m, 1 H), 3.78 (s, 3 H), 3.97- 4.12 (m, 1H), 4.14- 4.27 (m, 1 H), 5.93 (s, 1 H), 6.75 (t, J = 7.9 Hz, 1 H), 6.90(br d, J = 7.6 Hz, 1 H), 7.03 (br d, J = 8.6 Hz, 2 H), 7.31 (br d, J =7.8 Hz, 1 H), 7.77 (br d, J = 8.6 Hz, 2 H), 8.50 (br s, 1 H) DMSO-d6364.45 [M + H]+

TABLE 16 ESI Exam- MS ple Compound Name Structural formula ¹H NMR δ ppmSolvent m/z 69 11-[5-(4- Methoxyphenyl)- 2H-1,2,3-triazol- 4-yl]-1,10-diazatri- cyclo[6.3.1.0^(4,12)]do- deca- 4(12),5,7-trien-9- one

2.82-3.12 (m, 4 H), 3.77 (s, 3 H), 5.82 (s, 1 H), 6.75-6.89 (m, 1 H),6.93-7.11 (m, 2 H), 7.27 (br d, J = 7.3 Hz, 1 H), 7.37 (br d, J = 7.9Hz, 1 H), 7.64- 7.94 (m, 2 H), 8.16- 8.27 (m, 1 H), 15.02 (br s, 1 H)DMSO-d6 348.44 [M + H]+ 70 2-[5-(4- Ethoxyphenyl)- 2H-1,2,3-triazol-4-yl]-8-methyl- 2,3-dihydro-1H- quinazolin-4-one

1.33 (t, J = 6.9 Hz, 3 H), 2.04 (s, 3 H), 4.06 (q, J = 6.9 Hz, 2 H),6.06 (s, 1 H), 6.34 (br s, 1 H), 6.69 (t, J = 7.4 Hz, 1 H), 7.01 (d, J =8.6 Hz, 2 H), 7.15 (d, J = 6.9 Hz, 1 H), 7.56 (d, J = 7.3 Hz, 1 H), 7.72(d, J = 8.6 Hz, 2 H), 8.23 (br s, 1 H) DMSO-d6 350.36 [M + H]+ 712-[5-(4- Methoxyphenyl)- 2H-1,2,3-triazol- 4-yl]-8- (trifluoromethyl)-2,3-dihydro-1H- quinazolin-4-one

3.81 (s, 3 H), 6.08 (t, J = 3.3 Hz, 1 H), 6.85- 6.97 (m, 2 H), 7.04 (d,J = 8.9 Hz, 2 H), 7.58- 7.70 (m, 3 H), 7.97 (d, J = 7.3 Hz, 1 H), 8.62(d, J = 2.6 Hz, 1 H) DMSO-d6 390.33 [M + H]+ 72 8-Methyl-2-[4-[4-(2,2,2-trifluoro- ethoxy)phenyl]- 2H-1,2,3- triazol-5-yl]-2,3-dihydro-1H- quinazolin-4-one

2.04 (s, 3 H), 4.81 (q, J = 8.8 Hz, 2 H), 6.08 (s, 1 H), 6.37 (br s, 1H), 6.69 (t, J = 7.4 Hz, 1 H), 7.10-7.22 (m, 3 H), 7.56 (br d, J = 7.3Hz, 1 H), 7.79 (br d, J = 7.9 Hz, 2 H), 8.25 (br s, 1 H) DMSO-d6 404.28[M + H]+ 73 2-[4-[4- (Difluoro- methoxy)phenyl]- 2H-1,2,3-triazol-5-yl]-8- methyl-2,3- dihydro-1H- quinazolin-4-one

2.03 (s, 3 H), 6.10 (s, 1 H), 6.41 (br s, 1 H), 6.69 (t, J = 7.4 Hz, 1H), 6.99-7.35 (m, 4 H), 7.56 (br d, J = 9.6 Hz, 1 H), 7.87 (br d, J =8.2 Hz, 2 H), 8.28 (br s, 1 H) DMSO-d6 373.23 [M + H]+

TABLE 17 ESI Exa- MS mple Compound Name Structural formula ¹H NMR δ ppmSolvent m/z 74 8-Methyl-2-[5-(4- propoxyphenyl)- 2H-1,2,3-triazol-4-yl]-2,3-dihydro- 1H-quinazolin-4- one

0.98 (t, J = 7.4 Hz, 3 H), 1.73 (sxt, J = 7.1 Hz, 2 H), 2.04 (s, 3 H),3.96 (t, J = 6.6 Hz, 2 H), 6.06 (s, 1 H), 6.36 (br s, 1 H), 6.69 (t, J =7.6 Hz, 1 H), 7.02 (d, J = 8.6 Hz, 2 H), 7.15 (d, J = 6.9 Hz, 1 H), 7.56(d, J = 6.9 Hz, 1 H), 7.72 (br d, J = 8.6 Hz, 2 H), 8.25 (br s, 1 H)DMSO-d6 364.26 [M + H]+ 75 11-[5-(4- Ethoxyphenyl)- 2H-1,2,3-triazol-4-yl]-1,10- diaza- tricyclo[6.3.1.0^(4,12)]do- deca- 4(12),5,7-trien-9-one

1.32 (br t, J = 6.8 Hz, 3 H), 2.82-3.11 (m, 4 H), 3.97-4.13 (m, 2 H),5.82 (br s, 1 H), 6.81 (br t, J = 7.6 Hz, 1 H), 6.91-7.10 (m, 2 H), 7.27(br d, J = 7.3 Hz, 1 H), 7.37 (br d, J = 7.9 Hz, 1 H), 7.61- 7.90 (m, 2H), 8.26 (br s, 1 H), 15.03 (br s, 1 H) DMSO-d6 362.24 [M + H]+ 768-Methyl-2-[5-(4- propan-2- yloxyphenyl)-2H- 1,2,3-triazol-4-yl]-2,3-dihydro-1H- quinazolin-4-one

1.27 (d, J = 5.9 Hz, 6 H), 2.03 (s, 3 H), 4.66 (spt, J = 6.0 Hz, 1 H),6.06 (s, 1 H), 6.35 (br s, 1 H), 6.69 (t, J = 7.4 Hz, 1 H), 7.00 (d, J =8.6 Hz, 2 H), 7.15 (d, J = 7.3 Hz, 1 H), 7.56 (d, J = 7.3 Hz, 1 H), 7.70(br d, J = 8.6 Hz, 2 H), 8.24 (br s, 1 H) DMSO-d6 364.30 [M + H]+ 778-Methyl-2-[5-(4- trideuteriometh- oxy)phenyl)-2H- 1,2,3-triazol-4-yl]-2,3-dihydro-1H- quinazolin-4-one

2.03 (s, 3 H), 6.07 (br s, 1 H), 6.34 (br s, 1 H), 6.69 (t, J = 7.9 Hz,1 H), 7.02 (br d, J = 8.2 Hz, 2 H), 7.15 (br d, J = 7.3 Hz, 1 H), 7.56(br d, J = 7.9 Hz, 1 H), 7.66-7.83 (m, 2 H), 8.22 (br s, 1 H), 14.86 (brs, 1 H) DMSO-d6 339.28 [M + H]+

TABLE 18 ESI Exam- MS ple Compound Name Structural formula ¹H NMR δ ppmSolvent m/z 78 2-[4-[4-(2,2- Difluoroeth- oxy)phenyl]- 2H-1,2,3-triazol-5-yl]-8- methyl-2,3- dihydro-1H- quinazolin-4-one

2.03 (s, 3 H), 4.26- 4.45 (m, 2 H), 6.08 (br s, 1 H), 6.16-6.79 (m, 3H), 7.00-7.23 (m, 3 H), 7.56 (br d, J = 7.3 Hz, 1 H), 7.64- 7.90 (m, 2H), 8.22 (br s, 1 H), 14.90 (br s, 1 H) DMSO-d6 386.27 [M + H]+ 79 Ethyl2-[4-[4-(8- methyl-4-oxo-2,3- dihydro-1H- quinazolin-2-yl)-2H-1,2,3-triazol-5- yl]phenoxyacetate

1.21 (t, J = 7.3 Hz, 3 H), 2.02 (s, 3 H), 4.17 (q, J = 7.3 Hz, 2 H),4.82 (s, 2 H), 6.07 (br s, 1 H), 6.33 (br s, 1 H), 6.61- 6.75 (m, 1 H),6.94- 7.08 (m, 2 H), 7.15 (br d, J = 7.3 Hz, 1 H), 7.56 (br d, J = 7.6Hz, 1 H), 7.68-7.87 (m, 2 H), 8.22 (br s, 1 H), 14.87 (br s, 1 H)DMSO-d6 408.32 [M + H]+ 80 2-[5-(4- Ethoxyphenyl)- 2H-1,2,3-triazol-4-yl]-8-ethyl-2,3- dihydro-1H- quinazolin-4-one

1.01 (br t, J = 7.1 Hz, 3 H), 1.33 (t, J = 7.1 Hz, 3 H), 2.28-2.47 (m, 2H), 4.06 (q, J = 6.9 Hz, 2 H), 6.05 (br s, 1 H), 6.38 (br s, 1 H), 6.72(br t, J = 7.4 Hz, 1 H), 7.00 (br d, J = 7.9 Hz, 2 H), 7.15 (br d, J =7.3 Hz, 1 H), 7.57 (br d, J = 7.3 Hz, 1 H), 7.63- 7.83 (m, 2 H), 8.22(br DMSO-d6 364.38 [M + H]+ s, 1 H), 14.82 (br s, 1 H) 818-Ethyl-2-[4-(4- methoxyphenyl)- 2H-1,2,3-triazol-5- yl]-2,3-dihydro-1H-quinazolin-4- one

1.01 (br t, J = 7.4 Hz, 3 H), 2.30-2.17 (m, 2 H), 3.78 (s, 3 H), 6.05(br s, 1 H), 6.39 (br s, 1 H), 6.72 (br t, J = 7.4 Hz, 1 H), 7.02 (br d,J = 8.2 Hz, 2 H), 7.15 (br d, J = 7.3 Hz, 1 H), 7.57 (d, J = 7.9 Hz, 1H), 7.64-7.88 (m, 2 H), 8.22 (br s, 1 H), 14.84 (br s, 1 H) DMSO-d6350.35 [M + H]+

Example 822-[5-(4-Methoxyphenyl)-1H-pyrazol-4-yl]-2,3-dihydro-1H-quinazolin-4-one(CAS No. 1223730-46-8)

The title compound was prepared using the method of Example 1.

Example 832-[5-(4-Methoxyphenyl)-1H-pyrazol-4-yl]-1-methyl-2,3-dihydroquinazolin-4-one(CAS No. 1252133-21-3)

The title compound was prepared using the method of Example 1.

The compounds of Examples 84 to 87 shown in Table 19 below were preparedusing the methods of Examples 1 to 8 and methods based thereon, andmethods disclosed in literatures and methods based thereon.

TABLE 19 ESI Exam- MS ple Compound Name Structural formula ¹H NMR δ ppmSolvent m/z 84 11-[5-[4-(2,2- Difluoro- ethoxy)phenyl]- 2H-1,2,3-triazol-4-yl]-1,10- diazatri- cyclo[6.3.1.0^(4,12)]do- deca-4(12),5,7-trien-9- one

2.84-3.07 (m, 4 H), 4.34 (td, J = 14.7, 3.6 Hz, 2 H), 5.81 (s, 1 H),6.39 (tt, J = 54.4, 3.6 Hz, 1 H), 6.81 (t, J = 7.6 Hz, 1 H), 7.09 (d, J= 8.9 Hz, 2 H), 7.27 (d, J = 7.3 Hz, 1 H), 7.37 (d, J = 7.9 Hz, 1 H),7.85 (d, J = 8.9 Hz, 2 H), 8.27 (br s, 1 H) DMSO-d6 398.30 [M + H]+ 852-[4-(4- Methoxyphenyl)- 1H-pyrazol-3-yl]- 2,3-dihydro-1H-quinazolin-4-one

321.27 [M + H]+ 86 2-[4-(4- Methoxyphenyl)- 1H-pyrazol-3-yl]-1-methyl-2,3- dihydro-1H- quinazolin-4-one

335.29 [M + H]+ 87 2-[4-(4- Methoxyphenyl)- 1H-pyrazol-3-yl]-8-methyl-2,3- dihydro-1H- quinazolin-4-one

335.32 [M + H]+

(Test Example 1) Tankyrase Inhibitory Activity Test

The enzymatic activity of tankyrase 1 and the enzymatic activity oftankyrase 2 were measured by the ELISA method based on assessment ofauto-poly(ADP-ribosyl)ation to evaluate the tankyrase inhibitoryactivity of the compound prepared in each of Examples (test compound)(inhibitory activity against tankyrase 1 (TNKS1) and inhibitory activityagainst tankyrase 2 (TNKS2)). First, Flag tagged tankyrase 1(1,024-1,327aa, SAM+PARP) and tankyrase 2 (613-1,116aa, ANK5+SAM+PARP)were synthesized with a cell-free protein expression system, and dilutedwith a Tris buffer solution (50 mM Tris-HCl (pH 8.0), 150 mM NaCl, 10%glycerol). 50 μL of the diluted tankyrase 1 or tankyrase 2 was added toa plate with an anti-FLAG M2 monoclonal antibody immobilized thereon(Anti-FLAG High-Sensitivity M2-Coated Plate) (Sigma-Aldrich), and theplate was left standing overnight at 4° C. Thereafter, the plate waswashed four times with a PBS (PBST) buffer containing 0.1% Triton X-100.For Example 84, the Anti-FLAG High-Sensitivity M2-Coated Plate wasreplaced by an immunoplate (Thermo Fisher Scientific), tankyrase 1 ortankyrase 2 was immobilized on the immunoplate, and the immunoplate wasthen blocked with Blocking One (nacalai tesque), then washed with a PBS(PBST) buffer, and used as the following plate. With a control, thisreplacement was shown to have no impact on evaluation results.

Subsequently, the test compound diluted with an assay buffer (50 mMTris-HCl (pH 8.0), 4 mM MgCl₂, 0.2 mM DTT) (DMSO was used as a control)was added to each well of the plate, and the plate was left standing atroom temperature for 10 minutes. Thereafter, a biotin-labeled NADsolution (225 μM NAD, 25 μM 6-Biotin-17-NAD (Travigen, Inc.)) was addedand mixed as a donor substrate, and the mixture was reacted at 30° C.for 45 minutes. To blank wells was added distilled water instead of thebiotin-labeled NAD solution. After the reaction, the plate was washedwith a PBST buffer four times. Thereafter, HRP (horseradishperoxidase)-labeled streptavidin (Travigen, Inc.) was diluted with a PBSbuffer by 1,000 times, and added to each well, and the mixture wasreacted at room temperature for 20 minutes. The plate was washed with aPBST buffer four times, a chemiluminescent substrate solutionTACS-Sapphire (Travigen, Inc.) was then added to each well, the mixturewas reacted at room temperature for 20 minutes, and thechemiluminescence intensity was measured using a chemiluminescencemeasuring apparatus. For Example 84, the streptavidin was diluted by5,000 times, the chemiluminescent substrate solution TACS-Sapphire wasreplaced by an ELISA POD substrate TMB solution easy (nacalai tesque),the mixture was reacted at room temperature for 30 minutes, and thechemiluminescence intensity was measured using a chemiluminescencemeasuring apparatus. With a control, this replacement was shown to haveno impact on evaluation results.

The residual enzymatic activity in the presence of the test compound wasdetermined from the following expression. On the basis of the residualenzymatic activity at each of multiple concentrations of the testcompound, the enzyme inhibitory activity was calculated in terms of a50%-inhibition concentration (IC₅₀ value) using data analysis softwareOrigin (LightStone Corp.).Residual activity (%)={(chemiluminescence intensity with test compoundadded)−(chemiluminescence intensity of blank)}/{(chemiluminescenceintensity of control)−(chemiluminescence intensity of blank)}

For the TNKS1 (inhibitory activity against tankyrase 1) and the TNKS2(inhibitory activity against tankyrase 2) of each test compound asmeasured through the above-mentioned method, a test compound having anIC₅₀ value of less than 5 nM was rated “A”, a test compound having anIC₅₀ value of 5 nM or more and less than 20 nM was rated “B”, and a testcompound having an IC₅₀ value of 20 nM or more and less than 50 nM wasrated “C”. Tables 20 to 23 below show the results.

(Test Example 2) Cell Proliferation Inhibitory Activity Test

The cell proliferation inhibitory activity of the compound, which hadbeen prepared in each of Examples, against the human colorectal cancercell line COLO-320DM was evaluated by Celltiter-Glo Luminescent CellViability Assay (Promega Corporation; G7573). COLO-320DM cells werecultured in RPMI-1640 medium containing 2 mM glutamine (Wako PureChemical Industries, Ltd; 189-02025) supplemented with 10% fetal bovineserum. The cultured cells were washed with PBS, and then dissociatedwith trypsin/EDTA, and a cell solution with 3×10⁴ cells/mL was prepared.

Subsequently, the cell solution was seeded in a 96-well microplate(Thermo/Nunc Company; 136101) in an amount of 70 μL per well, andcultured overnight under the condition of 37° C. and 5% CO₂. Next day, atest compound solution obtained by diluting the test compound (DMSOsolution) with a cell culture medium (final concentration of DMSO was1%) was added in an amount of 10 μL per well, and the mixture wasreacted under the condition of 37° C. and 5% CO₂ for 96 hours (a 1% DMSOsolution was used as a control). Thereafter, a Celltiter-GloLuminescentCell Viability Assay reagent (Promega Corporation; G7573) was added inan amount of 80 μL per well, the mixture was stirred with a shaker for 2minutes while light was blocked with an aluminum foil, and the mixturewas incubated at room temperature for 10 minutes.

Thereafter, a luminescence signal was measured with a luminometer(Biotech Company; Synergy). The ratio of cell proliferation in eachcompound addition group to cell proliferation in a control groupcontaining no test compound solution, where cell proliferation in thecontrol group is 100%, was calculated and the value of a compoundconcentration necessary for suppressing the amount of residual cells to50% of that in the control (GI50) was calculated as the cytostaticactivity. For the COLO-320DM (cell proliferation inhibitory activityagainst COLO-320DM) of each test compound as measured through theabove-mentioned method, a test compound having a GI50 value of less than1 μM was rated “A”, a test compound having a GI50 value of 1 μM or moreand less than 10 μM was rated “B”, and a test compound having a GI50value of 10 μM or more was rated “C”. An unevaluated test compound wasdesignated as “NT”. Tables 20 to 23 show the results along with theresults of the tankyrase inhibitory activity test.

TABLE 20 Example TNKS1 TNKS2 COLO-320DM 1 C B NT 2 A A NT 3 B B C 4 B AC 5 B B C 6 C B B 7 C B C 8 A A A 9 C C NT 10 B A C 11 B A C 12 C B B 13C C C 14 C C C 15 B C C 16 C C C 17 C A C 18 C A C 19 B A C 20 C B C 21C B C 22 A A C 23 C C B 24 B B C 25 B C C

TABLE 21 Example TNKS1 TNKS2 COLO-320DM 26 C B C 27 A B C 28 A B B 29 BB B 30 B B B 31 B B C 32 C C C 33 C C C 34 C C B 35 C C C 36 C C C 37 CC C 38 C C B 39 C C C 40 C C C 41 C B B 42 C B B 43 A A C 44 B B B 45 AA B 46 A A B 47 C B C 48 C B B 49 C B C 50 B B C

TABLE 22 Example TNKS1 TNKS2 COLO-320DM 51 C C B 52 A B C 53 B B C 54 BA B 55 B A B 56 B B C 57 B A B 58 B A B 59 C A B 60 B B B 61 B B C 62 BB C 63 B B B 64 C B C 65 B A A 66 B A C 67 B B C 68 B B B 69 B B B 70 BA A 71 C C B 72 B B B 73 C C C 74 B B B 75 B B B

TABLE 23 Example TNKS1 TNKS2 COLO-320DM 76 C B B 77 B B A 78 B A B 79 BB C 80 B B A 81 B A B 82 B B C 83 B B B 84 B B C 85 B A B 86 A A B 87 AA B

As shown in Tables 20 to 23, the compounds prepared in Examples 1 to 87were all confirmed to have sufficient tankyrase inhibitory activity.

(Test Example 3) Microtubule Polymerization Inhibition Test

Using a microtubule polymerization reaction measurement kit(Cytoskeleton Inc.; BK011P), the microtubule polymerization inhibitoryactivity of the compound (test compound) prepared in each of Exampleswas evaluated on the basis of the standard protocol of the kit.Solutions with concentrations of 30 μM and 150 μM were prepared bydissolving the test compound in DMSO, and used as test compoundsolutions (with final concentrations of 3 μM and 15 μM, respectively).DMSO was used as a negative control solution, and vincristine (finalconcentration: 3 μM) was used as a positive control solution.

5 μL of the test compound solution or each control solution, and 50 μLof a microtubule-containing reaction mixture (1×Buffer 1; 1 mM GTP; 15%glycerol; and tubulin with a concentration of 2 mg/mL) were added to a96-well plate (Corning Costar Company; #3686) warmed to 37° C., and achange in fluorescence of the reaction solution was measured over 1hour. A higher fluorescence intensity means a higher degree ofprogression of polymerization of microtubules. The composition of Buffer1 and the fluorescence measurement conditions employed in the analysisare shown below.

<1× Buffer 1 (pH 6.9)>

80 mM Piperazine-N,N′-bis[2-ethanesulfonic acid] sequisodium salt; 2.0mM Magnesium chloride; 0.5 mM Ethylene glycol-bis (β-amino-ethylether)N,N,N′,N′-tetra-acetic acid; 10 μM fluorescent reporter

<Fluorescence Measurement Conditions>

Measurement wavelength: 360 nm (excitation wavelength) and 450 nm(emission wavelength)

Measurement time: 60 min (1 cycle/min)

Equipment used: Microplatereader SpectraMax M2 (Molecular DevicesCompany)

FIGS. 1A and 1B shows the results of conducting a microtubulepolymerization inhibition test of compounds (racemates) prepared inExamples 65, 69 and 70 (FIG. 1A shows the results of treatment at 3 μMand FIG. 1B shows the results of treatment at 15 μM). In FIGS. 1A and1B, the abscissa represents a reaction time (minutes) and the ordinaterepresents a fluorescence intensity. FIGS. 1A and 1B indicate that afterbeing mixed with the reaction mixture, the compounds (racemates)prepared in Examples 65, 69 and 70, as well as vincristine heretoforeknown as a microtubule polymerization inhibitor, showed a slowerincrease in fluorescence intensity as compared to the DMSO control.Thus, the compounds prepared in Examples 65, 69 and 70 were confirmed tohave high microtubule polymerization inhibitory activity.

INDUSTRIAL APPLICABILITY

As described above, the present invention can provide a novel compoundwhich has excellent tankyrase inhibitory activity and which is effectiveagainst diseases related to tankyrase and/or microtubules; apharmacologically acceptable salt thereof; and a cell proliferationinhibitor, a tankyrase inhibitor, a microtubule inhibitor and apharmaceutical composition which have excellent tankyrase inhibitoryactivity and/or microtubule inhibitory activity. The present inventioncan also provide a method for producing the novel compound and apharmacologically acceptable salt thereof; and an intermediate compounduseful for the production.

The invention claimed is:
 1. A composition comprising a compound of thefollowing formula (1) or a pharmacologically acceptable salt thereof:

wherein J¹ is CH or N, and J² is N; r represents 0 to 4; each R¹⁰¹ isthe same or different when r is 2 or more, and represents a halogenatom, a C₁₋₆ alkyl group optionally substituted with a halogen atom,OR¹¹¹, or a group represented by the formula: —N(R^(112a))—R^(112b),where R¹¹¹, R^(112a) and R^(112b) are each independently a hydrogen atomor a C₁₋₆ alkyl group; s represents 0 to 5; each R¹⁰² is the same ordifferent when s is 2 or more, and represents a halogen atom, a C₁₋₆alkyl group, OR¹¹³, a group represented by the formula:—N(R^(114a))—R^(114b), a group represented by the formula:—NH—C(═O)—R¹¹⁵, a group represented by the formula: —C(═O)—R¹¹⁶, anoptionally substituted aryl group, an optionally substituted heteroarylgroup, a nitro group, or a cyano group, where R¹¹³ is a hydrogen atom,an optionally substituted alkyl group, an optionally substituted arylgroup, an optionally substituted arylalkyl group, or an optionallysubstituted heteroaryl group, R^(114a) and R^(114b) are eachindependently a hydrogen atom or a C₁₋₆ alkyl group, R¹¹⁵ is anoptionally substituted alkyl group, an optionally substituted arylgroup, an optionally substituted heteroaryl group, or a grouprepresented by the formula: —NH—R¹²¹, R¹¹⁶ is an optionally substitutedalkyl group, an optionally substituted aryl group, an optionallysubstituted heteroaryl group, OR¹²², or a group represented by theformula: —N(R^(123a))—R^(123b)), R¹²¹ is an optionally substituted alkylgroup, an optionally substituted aryl group, or an optionallysubstituted heteroaryl group, R¹²² is a hydrogen atom, an optionallysubstituted alkyl group, an optionally substituted aryl group, or anoptionally substituted heteroaryl group, and R^(123a) and R^(123b) areeach independently a hydrogen atom, an optionally substituted alkylgroup, an optionally substituted aryl group, or an optionallysubstituted heteroaryl group, or R^(123a) and R^(123b) are linkedtogether to form a cyclic amine; R¹⁰³ represents a hydrogen atom, a C₁₋₆alkyl group, a C₃₋₆ cycloalkyl group, or a C₃₋₆ cycloalkyl C₁₋₆ alkylgroup; and R¹⁰¹ and R¹⁰³ are optionally linked together to form a five-to seven-membered hetero ring when R¹⁰¹ is present at the 8-position;and a diluent or a pharmaceutically acceptable excipient.
 2. Thecomposition of claim 1, wherein the compound of the formula (1) is acompound of the following formula (1a):

wherein J¹ is CH or N, and J² is N; r represents 0 to 4; each R¹⁰¹ isthe same or different when r is 2 or more, and represents a halogenatom, a C₁₋₆ alkyl group optionally substituted with a halogen atom,OR¹¹¹, or a group represented by the formula: —N(R^(112a))—R^(112b)),where R¹¹¹, R^(112a) and R^(112b) are each independently a hydrogen atomor a C₁₋₆ alkyl group; s represents 0 to 5; each R¹⁰² is the same ordifferent when s is 2 or more, and represents a halogen atom, a C₁₋₆alkyl group, OR¹¹³, a group represented by the formula:—N(R^(114a))—R^(114b), a group represented by the formula:—NH—C(═O)—R¹¹⁵, a group represented by the formula: —C(═O)—R¹¹⁶, anoptionally substituted aryl group, an optionally substituted heteroarylgroup, a nitro group, or a cyano group, where R¹¹³ is a hydrogen atom,an optionally substituted alkyl group, an optionally substituted arylgroup, an optionally substituted arylalkyl group, or an optionallysubstituted heteroaryl group, R^(114a) and R^(114b) are eachindependently a hydrogen atom or a C₁₋₆ alkyl group, R¹¹⁵ is anoptionally substituted alkyl group, an optionally substituted arylgroup, an optionally substituted heteroaryl group, or a grouprepresented by the formula: —NH—R¹²¹, R¹¹⁶ is an optionally substitutedalkyl group, an optionally substituted aryl group, an optionallysubstituted heteroaryl group, OR¹²², or a group represented by theformula: —N(R^(123a))—R^(123b), R¹²¹ is an optionally substituted alkylgroup, an optionally substituted aryl group, or an optionallysubstituted heteroaryl group, R¹²² is a hydrogen atom, an optionallysubstituted alkyl group, an optionally substituted aryl group, or anoptionally substituted heteroaryl group, and R^(123a) and R^(123b) areeach independently a hydrogen atom, an optionally substituted alkylgroup, an optionally substituted aryl group, or an optionallysubstituted heteroaryl group, or R^(123a) and R^(123b)) are linkedtogether to form a cyclic amine; R¹⁰³ represents a hydrogen atom, a C₁₋₆alkyl group, a C₃₋₆ cycloalkyl group, or a C₃₋₆ cycloalkyl C₁₋₆ alkylgroup; and R¹⁰¹ and R¹⁰³ are optionally linked together to form a five-to seven-membered hetero ring when R¹⁰¹ is present at the 8-position,with the exception of cases where J¹ represents CH, J² represents N, ris 0, R¹⁰³ is a hydrogen atom or a methyl group, R¹⁰² is present at thep-position, and R¹⁰² is a methoxy group.
 3. The composition of claim 1,wherein in the formula (1), r is 0; or r is 1, R¹⁰¹ is present at the7-position or the 8-position and R¹⁰¹ represents a C₁₋₃ alkyl groupoptionally substituted with a halogen atom, or a hydroxy group; or r is1, R¹⁰¹ is present at the 8-position and R¹⁰¹ and R¹⁰³ are linkedtogether to form a five- or six-membered hetero ring.
 4. The compositionof claim 1, wherein in the formula (1), R¹⁰³ represents a hydrogen atom,a C₁₋₃ alkyl group or a C₃₋₆ cycloalkyl C₁₋₃ alky group; or r is 1, R¹⁰¹is present at the 8-position and R¹⁰¹ and R¹⁰³ are linked together toform a five- or six-membered hetero ring.
 5. The composition of claim 1,wherein in the formula (1), s is 0; or s is 1 and R¹⁰² represents ahalogen atom, OR¹¹³ in which R¹¹³ is an optionally substituted C₁₋₃alkyl group, or an optionally substituted aryl group.
 6. The compositionof claim 1, wherein in the formula (1), J¹ and J² each represent N.
 7. Amethod for inhibiting cell proliferation, the method comprisingcontacting a cell with a compound of the following formula (1) or apharmacologically acceptable salt thereof:

wherein J¹ is CH or N, and J² is N; r represents 0 to 4; each R¹⁰¹ isthe same or different when r is 2 or more, and represents a halogenatom, a C₁₋₆ alkyl group optionally substituted with a halogen atom,OR¹¹¹, or a group represented by the formula: —N(R^(112a))—R^(112b),where R¹¹¹, R^(112a) and R^(112b) are each independently a hydrogen atomor a C₁₋₆ alkyl group; s represents 0 to 5; each R¹⁰² is the same ordifferent when s is 2 or more, and represents a halogen atom, a C₁₋₆alkyl group, OR¹¹³, a group represented by the formula:—N(R^(114a))—R^(114b), a group represented by the formula:—NH—C(═O)—R¹¹⁵, a group represented by the formula: —C(═O)—R¹¹⁶, anoptionally substituted aryl group, an optionally substituted heteroarylgroup, a nitro group, or a cyano group, where R¹¹³ is a hydrogen atom,an optionally substituted alkyl group, an optionally substituted arylgroup, an optionally substituted arylalkyl group, or an optionallysubstituted heteroaryl group, R^(114a) and R^(114b) are eachindependently a hydrogen atom or a C₁₋₆ alkyl group, R¹¹⁵ is anoptionally substituted alkyl group, an optionally substituted arylgroup, an optionally substituted heteroaryl group, or a grouprepresented by the formula: —NH—R¹²¹, R¹¹⁶ is an optionally substitutedalkyl group, an optionally substituted aryl group, an optionallysubstituted heteroaryl group, OR¹²², or a group represented by theformula: —N(R^(123a))—R^(123b), R¹²¹ is an optionally substituted alkylgroup, an optionally substituted aryl group, or an optionallysubstituted heteroaryl group, R¹²² is a hydrogen atom, an optionallysubstituted alkyl group, an optionally substituted aryl group, or anoptionally substituted heteroaryl group, and R^(123a) and R^(123b) areeach independently a hydrogen atom, an optionally substituted alkylgroup, an optionally substituted aryl group, or an optionallysubstituted heteroaryl group, or R^(123a) and R^(123b) are linkedtogether to form a cyclic amine; R¹⁰³ represents a hydrogen atom, a C₁₋₆alkyl group, a C₃₋₆ cycloalkyl group, or a C₃₋₆ cycloalkyl C₁₋₆ alkylgroup; and R¹⁰¹ and R¹⁰³ are optionally linked together to form a five-to seven-membered hetero ring when R¹⁰¹ is present at the 8-position;and a diluent or a pharmaceutically acceptable excipient.
 8. The methodof claim 7, wherein the compound of the formula (1) is a compound of thefollowing formula (1a):

wherein J¹ is CH or N, and J² is N; r represents 0 to 4; each R¹⁰¹ isthe same or different when r is 2 or more, and represents a halogenatom, a C₁₋₆ alkyl group optionally substituted with a halogen atom,OR¹¹¹, or a group represented by the formula: —N(R^(112a))—R^(112b),where R¹¹¹, R^(112a) and R^(112b) are each independently a hydrogen atomor a C₁₋₆ alkyl group; s represents 0 to 5; each R¹⁰² is the same ordifferent when s is 2 or more, and represents a halogen atom, a C₁₋₆alkyl group, OR¹¹³, a group represented by the formula:—N(R^(114a))—R^(114b), a group represented by the formula:—NH—C(═O)—R¹¹⁵, a group represented by the formula: —C(═O)—R¹¹⁶, anoptionally substituted aryl group, an optionally substituted heteroarylgroup, a nitro group, or a cyano group, where R¹¹³ is a hydrogen atom,an optionally substituted alkyl group, an optionally substituted arylgroup, an optionally substituted arylalkyl group, or an optionallysubstituted heteroaryl group, R^(114a) and R^(114b) are eachindependently a hydrogen atom or a C₁₋₆ alkyl group, R¹¹⁵ is anoptionally substituted alkyl group, an optionally substituted arylgroup, an optionally substituted heteroaryl group, or a grouprepresented by the formula: —NH—R¹²¹, R¹¹⁶ is an optionally substitutedalkyl group, an optionally substituted aryl group, an optionallysubstituted heteroaryl group, OR¹²², or a group represented by theformula: —N(R^(123a))—R^(123b), R¹²¹ is an optionally substituted alkylgroup, an optionally substituted aryl group, or an optionallysubstituted heteroaryl group, R¹²² is a hydrogen atom, an optionallysubstituted alkyl group, an optionally substituted aryl group, or anoptionally substituted heteroaryl group, and R^(123a) and R^(123b) areeach independently a hydrogen atom, an optionally substituted alkylgroup, an optionally substituted aryl group, or an optionallysubstituted heteroaryl group, or R^(123a) and R^(123b) are linkedtogether to form a cyclic amine; R¹⁰³ represents a hydrogen atom, a C₁₋₆alkyl group, a C₃₋₆ cycloalkyl group, or a C₃₋₆ cycloalkyl C₁₋₆ alkylgroup; and R¹⁰¹ and R¹⁰³ are optionally linked together to form a five-to seven-membered hetero ring when R¹⁰¹ is present at the 8-position,with the exception of cases where J¹ represents CH, J² represents N, ris 0, R¹⁰³ is a hydrogen atom or a methyl group, R¹⁰² is present at thep-position, and R¹⁰² is a methoxy group.
 9. The method of claim 7,wherein in the formula (1), r is 0; or r is 1, R¹⁰¹ is present at the7-position or the 8-position and R¹⁰¹ represents a C₁₋₃ alkyl groupoptionally substituted with a halogen atom, or a hydroxy group; or r is1, R¹⁰¹ is present at the 8-position and R¹⁰¹ and R¹⁰³ are linkedtogether to form a five- or six-membered hetero ring.
 10. The method ofclaim 7, wherein in the formula (1), R¹⁰³ represents a hydrogen atom, aC₁₋₃ alkyl group or a C₃₋₆ cycloalkyl C₁₋₃ alky group; or r is 1, R¹⁰¹is present at the 8-position and R¹⁰¹ and R¹⁰³ are linked together toform a five- or six-membered hetero ring.
 11. The method of claim 7,wherein in the formula (1), s is 0; or s is 1 and R¹⁰² represents ahalogen atom, OR¹¹³ in which R¹¹³ is an optionally substituted C₁₋₃alkyl group, or an optionally substituted aryl group.
 12. The method ofclaim 7, wherein in the formula (1), J¹ and J² each represent N.
 13. Themethod of claim 7, comprising inhibiting tankyrase by administering thecompound of the formula (1) or a pharmacologically acceptable saltthereof to a patient in need thereof.
 14. The method of claim 8,comprising inhibiting tankyrase by administering the compound of theformula (1a) or a pharmacologically acceptable salt thereof to a patientin need thereof.
 15. The method of claim 7, comprising inhibitingmicrotubules by administering the compound of the formula (1) or apharmacologically acceptable salt thereof to a patient in need thereof.16. The method of claim 8, comprising inhibiting microtubules byadministering the compound of the formula (1a) or a pharmacologicallyacceptable salt thereof to a patient in need thereof.
 17. The method ofclaim 7, comprising treating a disease attributable to tankyrase and/ormicrotubules by administering the compound of the formula (1) or apharmacologically acceptable salt thereof to a patient in need thereof.18. The method of claim 8, comprising treating a disease attributable totankyrase and/or microtubules by administering the compound of theformula (1a) or a pharmacologically acceptable salt thereof to a patientin need thereof.
 19. The method of claim 17, wherein the disease isselected from the group consisting of malignant tumor, Herpes simplexvirus infection, Epstein-Barr virus infection, pulmonary fibrosis,multiple sclerosis and amyotrophic lateral sclerosis.
 20. A compound ofthe following formula (1a) or a pharmacologically acceptable saltthereof:

wherein J¹ is N, and F is CH; r represents 0 to 4; each R¹⁰¹ is the sameor different when r is 2 or more, and represents a halogen atom, a C₁₋₆alkyl group optionally substituted with a halogen atom, OR¹¹¹, or agroup represented by the formula: —N(R^(112a))—R^(112b), where R¹¹¹,R^(112a) and R^(112b) are each independently a hydrogen atom or a C₁₋₆alkyl group; s represents 0 to 5; each R¹⁰² is the same or differentwhen s is 2 or more, and represents a halogen atom, a C₁₋₆ alkyl group,OR¹¹³, a group represented by the formula: —N(R^(114a))—R^(114b), agroup represented by the formula: —NH—C(═O)—R¹¹⁵, a group represented bythe formula: —C(═O)—R¹¹⁶ an optionally substituted aryl group, anoptionally substituted heteroaryl group, a nitro group, or a cyanogroup, where R¹¹³ is a hydrogen atom, an optionally substituted alkylgroup, an optionally substituted aryl group, an optionally substitutedarylalkyl group, or an optionally substituted heteroaryl group, R^(114a)and R^(114b) are each independently a hydrogen atom or a C₁₋₆ alkylgroup, R¹¹⁵ is an optionally substituted alkyl group, an optionallysubstituted aryl group, an optionally substituted heteroaryl group, or agroup represented by the formula: —NH—R¹²¹, R¹¹⁶ is an optionallysubstituted alkyl group, an optionally substituted aryl group, anoptionally substituted heteroaryl group, OR¹²², or a group representedby the formula: —N(R^(123a))—R^(123b), R¹²¹ is an optionally substitutedalkyl group, an optionally substituted aryl group, or an optionallysubstituted heteroaryl group, R¹²² is a hydrogen atom, an optionallysubstituted alkyl group, an optionally substituted aryl group, or anoptionally substituted heteroaryl group, and Ru^(123a) and R^(123b) areeach independently a hydrogen atom, an optionally substituted alkylgroup, an optionally substituted aryl group, or an optionallysubstituted heteroaryl group, or R^(123a) and R^(123b) are linkedtogether to form a cyclic amine; R¹⁰³ represents a hydrogen atom, a C₁₋₆alkyl group, a C₃₋₆ cycloalkyl group, or a C₃₋₆ cycloalkyl C₁₋₆ alkylgroup; and R¹⁰¹ and R¹⁰³ are optionally linked together to form a five-to seven-membered hetero ring when R¹⁰¹ is present at the 8-position.21. A composition comprising a compound of the following formula (1) ora pharmacologically acceptable salt thereof:

wherein J¹ is N, and J² is CH; r represents 0 to 4; each R¹⁰¹ is thesame or different when r is 2 or more, and represents a halogen atom, aC₁₋₆ alkyl group optionally substituted with a halogen atom, OR¹¹¹, or agroup represented by the formula: —N(R^(112a))—R^(112b)), where R¹¹¹,R^(112a) and R^(112b) are each independently a hydrogen atom or a C₁₋₆alkyl group; s represents 0 to 5; each R¹⁰² is the same or differentwhen s is 2 or more, and represents a halogen atom, a C₁₋₆ alkyl group,OR¹¹³, a group represented by the formula: —N(R^(114a))—R^(114b), agroup represented by the formula: —NH—C(═O)—R¹¹⁵, a group represented bythe formula: —C(═O)—R¹¹⁶, an optionally substituted aryl group, anoptionally substituted heteroaryl group, a nitro group, or a cyanogroup, where R¹¹³ is a hydrogen atom, an optionally substituted alkylgroup, an optionally substituted aryl group, an optionally substitutedarylalkyl group, or an optionally substituted heteroaryl group, R^(114a)and R^(114b) are each independently a hydrogen atom or a C₁₋₆ alkylgroup, R¹¹⁵ is an optionally substituted alkyl group, an optionallysubstituted aryl group, an optionally substituted heteroaryl group, or agroup represented by the formula: —NH—R¹²¹, R¹¹⁶ is an optionallysubstituted alkyl group, an optionally substituted aryl group, anoptionally substituted heteroaryl group, OR¹²², or a group representedby the formula: —N(R^(123a))—R^(123b), R¹²¹ is an optionally substitutedalkyl group, an optionally substituted aryl group, or an optionallysubstituted heteroaryl group, R¹²² is a hydrogen atom, an optionallysubstituted alkyl group, an optionally substituted aryl group, or anoptionally substituted heteroaryl group, and R^(123a) and R^(123b) areeach independently a hydrogen atom, an optionally substituted alkylgroup, an optionally substituted aryl group, or an optionallysubstituted heteroaryl group, or R^(123a) and R^(123b)) are linkedtogether to form a cyclic amine; R¹⁰³ represents a hydrogen atom, a C₁₋₆alkyl group, a C₃₋₆ cycloalkyl group, or a C₃₋₆ cycloalkyl C₁₋₆ alkylgroup; and R¹⁰¹ and R¹⁰³ are optionally linked together to form a five-to seven-membered hetero ring when R¹⁰¹ is present at the 8-position;and a diluent or a pharmaceutically acceptable excipient.
 22. A compoundof the following formula (1a) or a pharmacologically acceptable saltthereof:

wherein J¹ is CH or N, and J² is N; r represents 0 to 4; each R¹⁰¹ isthe same or different when r is 2 or more, and represents a halogenatom, a C₁₋₆ alkyl group optionally substituted with a halogen atom,OR¹¹¹, or a group represented by the formula: —N(R^(112a))—R^(112b),where R¹¹¹, R^(112a) and R^(112b) are each independently a hydrogen atomor a C₁₋₆ alkyl group; s represents 0 to 5; each R¹⁰² is the same ordifferent when s is 2 or more, and represents a halogen atom, a C₁₋₆alkyl group, OR¹¹³, a group represented by the formula:—N(R^(114a))—R^(114b), a group represented by the formula:—NH—C(═O)—R¹¹⁵, a group represented by the formula: —C(═O)—R¹¹⁶ anoptionally substituted aryl group, an optionally substituted heteroarylgroup, a nitro group, or a cyano group, where R¹¹³ is a hydrogen atom,an optionally substituted alkyl group, an optionally substituted arylgroup, an optionally substituted arylalkyl group, or an optionallysubstituted heteroaryl group, R^(114a) and R^(114b) are eachindependently a hydrogen atom or a C₁₋₆ alkyl group, R¹¹⁵ is anoptionally substituted alkyl group, an optionally substituted arylgroup, an optionally substituted heteroaryl group, or a grouprepresented by the formula: —NH—R¹²¹, R¹¹⁶ is an optionally substitutedalkyl group, an optionally substituted aryl group, an optionallysubstituted heteroaryl group, OR¹²², or a group represented by theformula: —N(R^(123a))—R^(123b)), R¹²¹ is an optionally substituted alkylgroup, an optionally substituted aryl group, or an optionallysubstituted heteroaryl group, R¹²² is a hydrogen atom, an optionallysubstituted alkyl group, an optionally substituted aryl group, or anoptionally substituted heteroaryl group, and R^(123a) and R^(123b) areeach independently a hydrogen atom, an optionally substituted alkylgroup, an optionally substituted aryl group, or an optionallysubstituted heteroaryl group, or R^(123a) and R^(123b) are linkedtogether to form a cyclic amine; R¹⁰³ represents a hydrogen atom, a C₁₋₆alkyl group, a C₃₋₆ cycloalkyl group, or a C₃₋₆ cycloalkyl C₁₋₆ alkylgroup; and R¹⁰¹ and R¹⁰³ are optionally linked together to form a five-to seven-membered hetero ring when R¹⁰¹ is present at the 8-position,with the exception of the case wherein J¹ represents CH, J² representsN, r is 0, R¹⁰³ is a hydrogen atom or a methyl group, and R¹⁰² ispresent at the p-position and is a methyl group, a methoxy group, achlorine atom, or a fluorine atom, or R¹⁰² is present at the in-positionand is a methoxy group.
 23. A method for inhibiting cell proliferation,the method comprising contacting a cell with a compound of the followingformula (1) or a pharmacologically acceptable salt thereof:

wherein J¹ is N, and J² is CH; r represents 0 to 4; each R¹⁰¹ is thesame or different when r is 2 or more, and represents a halogen atom, aC₁₋₆ alkyl group optionally substituted with a halogen atom, OR¹¹¹, or agroup represented by the formula: —N(R^(112a))—R^(112b), where R¹¹¹,R^(112a) and R^(112b) are each independently a hydrogen atom or a C₁₋₆alkyl group; s represents 0 to 5; each R¹⁰² is the same or differentwhen s is 2 or more, and represents a halogen atom, a C₁₋₆ alkyl group,OR¹¹³, a group represented by the formula: —N(R^(114a))—R^(114b), agroup represented by the formula: —NH—C(═O)—R¹¹⁵, a group represented bythe formula: —C(═O)—R¹¹⁶, an optionally substituted aryl group, anoptionally substituted heteroaryl group, a nitro group, or a cyanogroup, where R¹¹³ is a hydrogen atom, an optionally substituted alkylgroup, an optionally substituted aryl group, an optionally substitutedarylalkyl group, or an optionally substituted heteroaryl group, R^(114a)and R^(114b) are each independently a hydrogen atom or a C₁₋₆ alkylgroup, R¹¹⁵ is an optionally substituted alkyl group, an optionallysubstituted aryl group, an optionally substituted heteroaryl group, or agroup represented by the formula: —NH—R¹²¹, R¹¹⁶ is an optionallysubstituted alkyl group, an optionally substituted aryl group, anoptionally substituted heteroaryl group, OR¹²², or a group representedby the formula: —N(R^(123a))—R^(123b), R¹²¹ is an optionally substitutedalkyl group, an optionally substituted aryl group, or an optionallysubstituted heteroaryl group, R¹²² is a hydrogen atom, an optionallysubstituted alkyl group, an optionally substituted aryl group, or anoptionally substituted heteroaryl group, and R^(123a) and R^(123b) areeach independently a hydrogen atom, an optionally substituted alkylgroup, an optionally substituted aryl group, or an optionallysubstituted heteroaryl group, or R^(123a) and R^(123b) are linkedtogether to form a cyclic amine; R¹⁰³ represents a hydrogen atom, a C₁₋₆alkyl group, a C₃₋₆ cycloalkyl group, or a C₃₋₆ cycloalkyl C₁₋₆ alkylgroup; and R¹⁰¹ and R¹⁰³ are optionally linked together to form a five-to seven-membered hetero ring when R¹⁰¹ is present at the 8-position;and a diluent or a pharmaceutically acceptable excipient.
 24. A compoundof the following formula (1a) or a pharmacologically acceptable saltthereof:

wherein J¹ is N, and J² is N; r represents 0 to 4; each R¹⁰¹ is the sameor different when r is 2 or more, and represents a halogen atom, a C₁₋₆alkyl group optionally substituted with a halogen atom, OR¹¹¹, or agroup represented by the formula: —N(R^(112a))—R^(112b), where R¹¹¹,R^(112a) and R^(112b) are each independently a hydrogen atom or a C₁₋₆alkyl group; s represents 0 to 5; each R¹⁰² is the same or differentwhen s is 2 or more, and represents a halogen atom, a C₁₋₆ alkyl group,OR¹¹³, a group represented by the formula: —N(R^(114a))—R^(114b), agroup represented by the formula: —NH—C(═O)—R¹¹⁵, a group represented bythe formula: —C(═O)—R¹¹⁶, an optionally substituted aryl group, anoptionally substituted heteroaryl group, a nitro group, or a cyanogroup, where R¹¹³ is a hydrogen atom, an optionally substituted alkylgroup, an optionally substituted aryl group, an optionally substitutedarylalkyl group, or an optionally substituted heteroaryl group, R^(114a)and R^(114b) are each independently a hydrogen atom or a C₁₋₆ alkylgroup, R¹¹⁵ is an optionally substituted alkyl group, an optionallysubstituted aryl group, an optionally substituted heteroaryl group, or agroup represented by the formula: —NH—R¹²¹, R¹¹⁶ is an optionallysubstituted alkyl group, an optionally substituted aryl group, anoptionally substituted heteroaryl group, OR¹²², or a group representedby the formula: —N(R^(123a))—R^(123b), R¹²¹ is an optionally substitutedalkyl group, an optionally substituted aryl group, or an optionallysubstituted heteroaryl group, R¹²² is a hydrogen atom, an optionallysubstituted alkyl group, an optionally substituted aryl group, or anoptionally substituted heteroaryl group, and R^(123a) and R^(123b) areeach independently a hydrogen atom, an optionally substituted alkylgroup, an optionally substituted aryl group, or an optionallysubstituted heteroaryl group, or R^(123a) and R^(123b) are linkedtogether to form a cyclic amine; R¹⁰³ represents a hydrogen atom, a C₁₋₆alkyl group, a C₃₋₆ cycloalkyl group, or a C₃₋₆ cycloalkyl C₁₋₆ alkylgroup; and R¹⁰¹ and R¹⁰³ are optionally linked together to foiin a five-to seven-membered hetero ring when R¹⁰¹ is present at the 8-position.